Apparatus for directed intranasal administration of a composition

ABSTRACT

Methods, kits, apparatus, and compositions for inhibiting a cerebral neurovascular disorder, a muscular headache, or cerebral inflammation in a human patient are provided. The methods comprise intranasally administering to the patient a pharmaceutical composition comprising a local anesthetic, and preferably a long-acting local anesthetic ingredient. A composition useful for practicing the methods of the invention is described which comprises at least one local anesthetic in a pharmaceutically acceptable carrier, wherein the composition is formulated for intranasal delivery. Cerebral neurovascular disorders include migraine and cluster headache. Muscular headaches include tension headaches and muscle contraction headaches. A kit comprising the composition and an intranasal applicator and a method of systemically delivering a pharmaceutically active agent to an animal are also included in the invention. Apparatus for directed intranasal administration of the compositions of the invention and for performing the methods of the invention are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. ApplicationSer. No. 09/492,946, filed Jan. 27, 2000, which is entitled to prioritypursuant to 35 U.S.C. §119(e) to U.S. Provisional Application No.60/117,398, filed Jan. 27, 1999, a continuation-in-part of U.S.Application Ser. No. 09/737,302, filed Dec. 15, 2000, which is entitledto priority pursuant to 35 U.S.C. §119(e) to U.S. ProvisionalApplication No. 60/170,817, filed Dec. 15, 1999, and acontinuation-in-part of U.S. Application No. 09/118,615, filed Jul. 17,1998, which is entitled to priority pursuant to 35 U.S.C. §119(e) toU.S. Application Ser. No. 08/897,192, filed Jul. 21, 1997, converted toU.S. Provisional Application No. 60/090,110, to U.S. ProvisionalApplication No. 60/072,845, filed Jan. 28, 1998, and to U.S. ProvisionalApplication No. 60/084,559, filed May 6, 1998.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] Not applicable.

REFERENCE TO A MICROFICHE APPENDIX

[0003] Not applicable.

BACKGROUND OF THE INVENTION

[0004] This invention relates to compositions, kits, methods, andapparatus for inhibiting muscular headaches and cerebral neurovasculardisorders including, but not limited to, neurovascular headaches,migraines, cluster headaches, tinnitus, cerebrovascular spasm, ischemicdisorders, seizures, central neuraxial motor, sensory, and cognitivedeficits, degenerative, traumatic, or infectious lesions of the centralnervous system, and cephalic inflammation including, but not limited to,meningeal inflammation, intracranial inflammation, extracranialinflammation. The invention also relates to apparatus and methods fordirecting intranasal administration of a composition to a selectedportion of the nasal cavity, such as the superior portion or thedorsonasal portion.

[0005] Headache is a common symptom of numerous diseases and disordersincluding, but not limited to, migraine, muscle tension, systemic orintracranial infection, intracranial tumor, head injuries, severehypertension, cerebral hypoxia, certain diseases of the eyes, nose,throat, teeth, and ears, and head pain for which no cause can bedetermined.

[0006] Infrequent headaches can often be determined to result fromcauses attributable to a particular experience of a patient, such asfatigue, fever, alcohol ingestion, muscle contraction, tension, or thelike. The cause of persistent or recurrent headaches is often difficultto determine. Persistent or recurrent headaches include, but are notlimited to, muscular headaches, such as tension or muscle contractionheadaches, and neurovascular headaches, such as migraines and clusterheadaches.

[0007] Cerebral neurovascular disorders (CNvDs) are characterized by oneor more disturbances in the normal functioning of at least one componentof the cerebral vascular or nervous system in a human. CNvDs include,for example, migraine, cluster headaches, other headaches ofneurovascular etiology, tinnitus, and cerebrovascular spasm. Humanpatients afflicted with a CNvD experience a single episode of thedisorder, recurrent episodes, persistent episodes, or some combinationof these patterns. An individual episode is designated an acute CNvD.

[0008] Many CNvDs, such as cerebral vascular accidents, reversibleischemic neurological defects, and transient ischemic attacks (TIA), areassociated with functional cerebral ischemia. These are oftennonhemorrhagic and of thrombotic, embolic, and vasospastic etiologies.Furthermore, intracranial vasospasm commonly afflicts patients who haveexperienced an acute cerebral ischemic event such as a stroke and isoften problematic following thrombolytic therapy. Numerous symptomsoccur during and after acute cerebral ischemic events. Indeed,neurovascular headaches have a vasomotor component to them, which may beresponsible for certain or many of the symptoms experienced by patientswho are afflicted with prolonged or recurrent neurovascular headachessuch as migraines and cluster headaches.

[0009] It has been theorized that headaches of neurovascular etiology,such as migraines, for example, result from release of neurotransmittersby trigeminal nerves, which innervate cerebral blood vessels (Moskowitzet al., 1979, Lancet 2:883-885). When disturbed, the trigeminal ganglionis capable of antidromic release of excitatory and otherneurotransmitters that initiate sterile inflammation (Demarin et al.,1994, Funct. Neurol. 9:235-245; Moskowitz, 1984, Ann. Neurol.16:157-168; Moskowitz, 1993, Neurol. 43(Suppl. 3):S16-S20). Studies oftrigeminal stimulation, cerebral blood flow, and neuropeptides in animalmodels and in humans provide support for this theory (Goadsby et al.,1993, Ann. Neurol. 33:48-56; Goadsby et al., 1991, Headache, 31:365-370;Goadsby et al., 1990, Ann. Neurol. 28:183-187; Edvinsson et al., 1994,Cephalalgia 14:88-96). It has been postulated that changes in cerebralblood flow that are triggered by trigeminal stimulation are mediated bythe sphenopalatine ganglion (hereinafter, the “SPG”) Goadsby et al.,1987, Am J. Physiol. 22:R270-R274; Lambert et al. 1984, J. Neurosurg.61:307-315; Walters et al., 986, Stroke 17:488-494; Suzuki et al., 1989Neuroscience 30:595-604).

[0010] Another theory posits that nitric oxide is a causative moleculeof headaches of neurovascular etiology (Olesen et al., 1995, Cephalalgia15:94-100). Because the SPG and related postsynaptic and neurovascularstructures contain many cells which express nitric oxide synthetase, theSPG mediates the changes in cerebral blood flow that are triggered bytrigeminal stimulation, according to this model.

[0011] Regardless of whether a neurotransmitter, nitric oxide, both, orneither are the causative agent of headaches of neurovascular etiology,it is clear that the SPG and other dorsonasal nerve structures are keycomplex structures for targeting the treatment of headaches ofneurovascular origin, such treatment including, but not being limited tothe treatment of the pain associated with such headaches. Methods oftreating headaches of neurovascular etiology which have been describedin the prior art have not provided sustained and effective relief fromacute neurovascular headache episodes.

[0012] Other researchers have observed meningeal inflammation in thevicinity of head pain associated with migraine (Pappagallo et al., April1999 presentation, Meeting of the American Academy of Neurology,Toronto, Canada). Certain aspects of head pain associated with migraine(e.g., throbbing headache, nausea, and sensitivity to light and sound)are similar to head pain associated with meningitis. Single photonemission computerized tomography confirmed enhanced permeability ofmeningeal blood vessels in patients experiencing migraine, which is acommon finding among meningitis patients. It is believed by the inventorthat meningeal inflammation may be associated with stimulation of, ortransmission by way of, the trigeminal nerve and related neuronalstructures.

[0013] Migraine

[0014] Migraine is a disorder characterized by persistent headache,which may be severe, which may be associated with visual andgastrointestinal disturbances, and which may also be recurrent. Incertain cases, visual changes (designated “aura” by some practitioners)or other symptoms precede the onset of a migraine. Such prodromalsymptoms may be due to intracranial vasoconstriction. The preciseetiology of migraine is unknown. Reported evidence suggests that agenetically transmitted functional disturbance of intra- andextracranial circulation may be involved. Regional alterations incerebral blood flow attributable to intracranial arterial vasodilationare known to accompany headache associated with migraine. Someinvestigators have attributed head pain associated with a migraine tosubstances released as a result of or associated with dilation of scalparteries during an acute migraine episode (e.g., Berkow et al., ed.,1992, The Merck Manual of Diagnosis and Therapy, Merck ResearchLaboratories, Rahway, N.J., pp. 1425-1426).

[0015] Prodromal symptoms of an acute migraine episode include, but arenot limited to, depression, irritability, restlessness, anorexia,scintillating scotomas, visual changes such as perception of stars orzig-zag lines, paresthesias, and hemiparesis. These prodromal symptomsmay disappear shortly before the migraine is manifested, or may persistuntil or after the onset of the migraine.

[0016] The head pain associated with migraine may be unilateral orgeneralized. Nausea, vomiting, and photophobia often accompanymigraines. Symptoms generally follow a pattern in an individual patient,except that unilateral head pain may not always be on the same side.Patients afflicted with migraine may experience migraines with afrequency between daily and only once in several months. An untreatedacute migraine episode may endure for a long period, such as hours ordays. Approximately 17% of adult women and approximately 6% of adult menexperience migraines each year (Stewart et al., 1994, Neurol. (Suppl.4):S17-S23; Lipton et al., 1993 Neurology 43(Suppl. 3):S6-S10 ;Osterhaus et al., 1992, PharmacoEconomics 2:67-76). Migraines may occurat any age, but usually begin between ages 10 and 30. Migraines oftenpartially or completely remit after age 50. Frequently, a history ofmigraines may be ascertained in the genealogy of a patient afflictedwith migraine.

[0017] Various nonspecific medical and surgical procedures have beenrecommended to decrease the frequency of recurrence of migraines. Suchprocedures include surgery, counseling, participation of the patient inbiofeedback procedures, and administration of methysergide, propanolol,a calcium channel blocker such as verapamil, an ergotamine preparationsuch as dihydroergotamine, or a serotonin receptor agonist such assumatriptan. Some procedures to decrease the frequency of recurrence ofmigraines may offer benefit to certain patients, but are not useful foralleviating the pain associated with an acute migraine episode once ithas begun.

[0018] Treatments which have been recommended for the treatment of anacute migraine episode include administration of aspirin, codeine, aserotonin agonist such as sumatriptan, ergot, ergotamine, caffeine, anarcotic, butorphanol tartrate, meperidine, or a combination of thesecompounds. Administration of any combination of these compounds has notoffered satisfactory or sustained relief from the pain or other symptomsassociated with an acute migraine episode in many patients. Furthermore,numerous side effects have been reported to accompany administration ofthese compounds, including dizziness, nausea, somnolence, fatigue, chestpain, cardiac infarction, hypertension, hypertensive crisis, chest-,face-, and neck-hyperemia, gastrointestinal upset, sedation, drugdependence, and the like. In addition, certain of these compounds arecontraindicated for numerous patients such as pregnant women, nursingwomen, patients using monoamine oxidase inhibitors, patients having ahistory of ischemic heart disease, ulcer, gastritis, kidney disease,liver disease, and other diseases.

[0019] Currently popular migraine treatments involve administration of apharmaceutically active agent which interacts with a serotonin receptoron cerebral arterial surfaces (Goadsby, 1995, In: Migraine: Pharmacologyand Genetics, Sandler et al., Eds., pp. 67-81; Cambridge et al., 1995,Brit. J. Pharmacol. 114:961-968; Ferrari et al., 1995, Euro. J. Neurol.2:5-21). Serotonin receptor agonists include sumatriptan (IMITREX™,Glaxo Wellcome Inc., Research Triangle NC), zolmitriptan (ZOMIG™, ZenecaPharmaceuticals, Wilmington, Del.), and rizatriptan (MAXALT™, Merck &Co., West Point, Pa.). Serotonin receptor agonists are believed toproduce relief from an acute migraine episode by causing resumption ofregulated cranial blood flow, thereby halting the acute migraine episode(Hamel et al., 1993 Mol. Pharmacol. 44:242-246). However, administrationof serotonin receptor agonists is inefficient via intravenous, oral, andintrarectal gavage routes. These routes of administration result insystemic agonist distribution, which increases the availability of theagonist to hepatic tissue and to other sites where the agonists aremetabolized. Furthermore, systemic distribution of one of an agonistresults in distribution of the agonist to sites where the agonistproduces undesirable side effects (Saper, 1997, Headache 37(Suppl.1):S1-S14). Therefore, it would be advantageous to administer an agentwhich does not require systemic delivery.

[0020] Intranasal administration of lidocaine for the relief of painassociated with migraines has been investigated in a non-controlledstudy by Kudrow et al. (1995, Headache, 35:79-82). In that study, manypatients experienced no relief and were on migraine prophylacticmedication. In a controlled study, Maizels and co-workers evaluated theeffectiveness of intranasally-administered lidocaine, a shorter-actinglocal anesthetic, for treatment of acute migraine episodes (Maizels etal., 1996, J. Amer. Med. Assoc. 276:319-321). High concentrations oflidocaine administered intranasally decreased head pain within fifteenminutes in 55% of the patients so treated. However, significant pain andassociated symptoms persisted in many of these patients followingtreatment. A significant number of patients required further treatmentwith other types of migraine medication to attain acceptable relief.Furthermore, the acute migraine episode frequently rebounded or relapsedearly after treatment, usually within the first hour.

[0021] Cluster Headaches

[0022] A cluster headache comprises a headache which is characterized byrecurrent episodes of unilateral excruciating pain, usually occurring onthe same side of the head of a patient. These headaches are typicallyoculofrontal or oculotemporal, with occasional radiation to the upperjaw, and are described as being of a boring, non-throbbing nature.Associated with the head pain are one or more autonomic accompaniments,including conjunctival injection, nasal congestion, lacrimation,rhinorrhea, body temperature elevation, vasodilation on the same side asthat on which the pain is experienced, and edema beneath the eye. Acluster headache is usually of short duration, persisting for betweenfifteen and ninety minutes, and tends to occur in clusters—typically afew times a day for a period of six to twelve weeks. Months or years maypass between the clusters of headaches. Because headaches which appearto be identical to spontaneous cluster headaches may be induced bysubcutaneous injection of histamine diphosphate, cluster headaches arealso known as histamine headaches. Headaches having sensory similarityto cluster headaches may also be induced by administration ofnitroglycerin to a human patient, for example by sublingualadministration of 0.4 milligrams of nitroglycerin.

[0023] Methods which have been investigated for treating clusterheadaches include administration of methysergide, a vasoconstrictor, acorticosteroid, oxygen, indomethacin, and intranasal administration ofcocaine, which is a toxic shorter-acting local anesthetic withpronounced central effects and a vasoconstrictor, or lidocaine, which isalso a shorter-acting local anesthetic (Barre, 1982, Headache, 22:69-73;Kittrelle et al., 1985, Arch. Neurol. 42:496-498). These investigationshighlight that shorter-acting local anesthetics were effective to abortpain associated with a single individual headache episode that is onlyone of several headache episodes comprising a cluster headache,sometimes referred to as a cluster period. Large amounts of drug andrepeated dosings were required to achieve these results. However, noinvestigation was made by those investigators of the ability of theseshorter-acting local anesthetics to provide relief from all, or evenmore than one, of the typically short-duration headaches associated witha single cluster headache period. Clinically, intranasal administrationof lidocaine has proven to be disappointing and is not widely used, noris it included in recognized cluster headache treatment protocols.

[0024] Tinnitus

[0025] More than 37 million Americans are afflicted with tinnitus.Tinnitus is a condition characterized by a ringing, buzzing, roaring, orclicking sound perceived by a patient, a person observing the patient,or both, which seems to originate from the ear of the patient. Objectivetinnitus is characterized by noise originating from the ear of a patientwhich can be perceived by a person examining the patient, while noiseassociated with subjective tinnitus can be perceived only by thepatient. There are currently no truly effective treatment optionsavailable for tinnitus, which has been associated with instances ofsuicide in patients afflicted therewith. Treatment methods which havebeen attempted include surgical decompression of the eighth nerve, useof specialized hearing aids which mask the tinnitus, and infusion ofdrugs directly into areas of the brain involved in auditory sensoryprocessing. None of these treatment methods has proven routinelyeffective.

[0026] Intra- and Extracranial Vasospasm

[0027] Intra- and extracranial vasospasm, hereinafter referred to as“cerebrovascular spasm,” results from contraction of smooth muscletissue of a cerebral blood vessel. Cerebrovascular spasm interferes withcerebral blood supply and is associated with numerous symptoms,including muscle paralysis, visual changes, speech changes, and numerousischemic symptoms of stroke. Vascular muscle tone is modulated byneural, humoral and local factors.

[0028] Disorders Manifested During or After and Associated with an AcuteIschemic Event

[0029] Causes of acute ischemic events include occlusive (i.e.,thrombotic or embolic) processes, as well as vasospastic and otherphysiological processes and disorders, following the onset of which theaffected tissue is insufficiently supplied with oxygenated blood.Manifestations during or after such events include, for example, tissuedamage or death, vasospasm, vasodilation, vasomotor instability, muscleweakness, dysphasia, dysphonia, cognitive impairment, autonomicimbalance, and the like. These disorders may be alleviated by increasingoxygenated blood supply to the ischemic tissue. Increased blood supplyto ischemic cerebral tissue may be effected, for example, by inducingdilation of an occluded cerebral blood vessel. Further by way ofexample, such increased blood supply may be effected by dilation ofcerebral blood vessels proximal to an occluded vessel by increasing theflow of oxygenated blood or by increasing the pressure gradient acrossthe occlusion, thereby decreasing the amount of watershed ischemia,decreasing the amount of damaged cerebral tissue, and increasing theamount of cerebral tissue which may be salvaged. Furthermore,facilitating venous drainage, by venodilation, decreases venous backpressure and increases forward flow of oxygenated blood.

[0030] Prior art methods of treating such disorders exhibit seriouslimitations. Thrombolytic therapy, for instance, is known to beeffective to decrease the severity of cerebral damage caused by certainocclusive strokes if the therapy is performed soon enough after theonset of the occlusion. However, cerebrovascular spasm frequentlyfollows, and decreases the success of the procedure and adverselyaffects patient outcome. A method of reducing the severity of an acutecerebral ischemic event by increasing early blood flow to the ischemicarea and decreasing vasospasm is needed.

[0031] Anatomy of the Nasal Cavity

[0032] The structures associated with the nasal cavity are described,for example, in Williams et al. (eds., 1980, Gray's Anatomy, 36th ed.,W.B. Saunders Co., Philadelphia, 1062-1065), especially at FIGS. 3.78,3.79, 3.80, 7.239, and 7.240 and the accompanying text. FIG. 1 herein isa diagram depicting the approximate location of the SPG in relation tothe nasal cavity of a human.

[0033] The SPG is, in some texts, designated the “pterygopalatineganglion.” The position, origin, branches, and distribution of the SPGmay be understood by examining FIGS. 7.177, 7.178, 7.179, and 7.181 andthe accompanying text in Williams et al. (supra).

[0034] As the cited figures and text describe, the SPG is located belowa region of epithelium in the posterior portion of the nasal cavity,inferior to and including the spheno-ethmoidal recess, and is thereforenot readily accessible via the nostril.

[0035] Ropivacaine is a recently introduced amino amide local anestheticthat is commercially available as the S(levo)-enantiomer (Lee et al.,1989, Anesth. Analg. 69:736-738). Ropivacaine allows differential nerveblock and exhibits intermediate distribution and clearance and a bettersystemic toxicity profile compared with other similar relatively longacting potent local anesthetics. In addition, ropivacaine also exhibitsinherent vasoactive properties (dejong, 1995, Reg. Anesth. 20:474-481;Santos et al., 1990, Anesth. Analg. 70:262-266). Ropivacaine-HCl iscommercially available as 0.25%, 0.5%, 0.75% and 1.0% (w/v) solution(NAROPIN™, Astra USA, Inc., Westborough, Mass.), and has been described,for example in international patent application publication number WO85/00599.

[0036] Local anesthetics are known to block the generation and theconduction of nerve impulses, presumably by increasing the threshold forelectrical excitation in the nerve, by slowing the propagation of nerveimpulses, and by reducing the rate of rise of the action potential ofthe nerve. In general, the progression of anesthesia is related to thediameter, degree of myelination, and conduction frequency and velocityof affected nerve fibers. Generally, the order of loss of nerve functionis as follows: (1) sympathetic and parasympathetic function, temperatureand pain, and (2) touch, and, where applicable, (3) proprioception, and(4) skeletal muscle tone.

[0037] The rate of systemic absorption in a patient of a localanesthetic is dependent upon the total dose, the concentration, and theidentity of the local anesthetic administered to the patient, the routeof administration, the vascularity of the site of administration, andthe presence or absence of vasoconstrictors such as epinephrine in theanesthetic composition. A dilute concentration of epinephrine (e.g.,1:200,000 or 5 micrograms per milliliter) usually reduces the rate ofabsorption and peak plasma concentration of the local anesthetic,sometimes prolonging the duration of the anesthetic effect.

[0038] The duration of the anesthetic effect at a given site ofadministration of a local anesthetic is dependent upon the total dose,the concentration, and the identity of the local anesthetic administeredto the patient, the rate of systemic absorption, and often the presenceor absence of a vasoconstricting or other agent in the anestheticcomposition.

[0039] Systemic administration of a local anesthetic is not a practicalmethod for delivery of the local anesthetic to provide lasting relief ofheadache pain in a human patient, due to known adverse reactions,occasionally including acute emergencies, associated therewith.

[0040] There remains a significant unmet need for effective methods oftreating acute CNvDs such as persistent and recurrent headaches ofneurovascular etiology, including migraines and cluster headaches.Particularly needed are compositions and methods which are effective forinhibiting an acute neurovascular headache episode.

[0041] Muscular Headaches

[0042] Muscular headaches are very common in the adult population. It isestimated that between about 3% and about 5% of patients who experiencea muscular headache are afflicted with chronic muscular headaches, bywhich is meant that the muscular headache occurs more than fifteen daysper month for a period of at least about six months. Analgesic addictionis a recognized problem in the treatment of patients afflicted withchronic muscular headaches.

[0043] Muscular headaches may be acute, as is the case for typicalepisodic tension headaches, which are related to contraction of musclesof the head and neck. Sustained contractions of skeletal muscles of thehead, neck, face, and shoulders are associated with concurrent localchemical changes within skeletal muscle, and may give rise to pain. Thepain may be localized or it may be referred, which means that the painis perceived at a body location different than the location of musclecontraction. Muscle contraction headaches may also be chronic andassociated with depression or with one or more other psychologicalproblems. Muscle contraction headaches may also be associated withanatomic factors such as cervical arthritis, temporomandibular jointdisorders, irritating lesions, pressure and mechanical stress, eyestrain, or emotional stress or disorders.

[0044] Muscular headaches, including muscle contraction headaches andtension headaches, are recognized as the most common category ofrecurring head pain. In distinction from migraines, they are usuallybilateral, often with occipital nuchal, temporal, or frontalpredominance or with diffuse extension over the top of the cranium. Thepain may be located in the back of the head and neck as well. Unlikemigraine pain, the pain associated with a muscular headache is usuallydescribed as squeezing and vise-like in nature. Nausea, photophobia, andphonophobia are not generally associated with muscular headacheepisodes. The onset of a muscular headache episode is more gradual thanthe onset of a migraine or cluster headache episode, and muscularheadache episodes are not generally associated with auras or prodromalsymptoms. The onset of muscular headache episodes does not appear to beassociated with physical activity by the patient. Once established, amuscular headache episode may persist, perhaps with minimal fluctuationsin intensity, for weeks or months. Muscular headache is recognized asbeing present all day, day after day.

[0045] Although patients afflicted with migraine may be awaked fromsleep, patients afflicted with a chronic muscular headache generallysleep undisturbed and perceive development or intensification of theheadache soon after waking. About a third of patients afflicted with amuscular headache exhibit symptoms of depression. Migraine headaches maybe complicated by tension headaches which persist and arouse fears ofmass lesions, thereby leading to the performance of unnecessarydiagnostic workups in many patients.

[0046] Muscular headaches are recognized as being a distinct class ofheadaches, distinguishable from headaches such as migraines or clusterheadaches.

[0047] Muscular headaches are, in part, related to sustained contractionof the skeletal muscles of the scalp, face, neck, and shoulders.Sustained muscle contraction is related to local pathology, centralinfluences, and multisystem modulation, and involves gamma efferentneuronal muscle spindle activation. Related monosynaptic conductionthrough the ventral horn augments both efferent neuronal discharge andmuscle contraction. A cycle of pain, muscle spasm, local chemicalchanges, neural excitability, skeletal muscle blood vessel compressionor spasm, and anxiety ensues. All types of persistent headaches lead tosustained cranial muscle contraction, but pain resulting from this typeof sustained contraction is typified by an aching sensation, rather thanby the characteristic squeezing pain associated with muscular headaches.Sometimes, surface electromyograph recordings of the craniocervicalmuscles show no evidence of persistent contraction. It is thereforewidely suspected that muscular headaches are not caused solely bysustained cranial muscle contraction.

[0048] Generally, the pain associated with a muscular headache episodeis mild to moderate in severity, although the pain becomes severe inmany patients. Relaxation, massage, and common analgesic medicationssuch as aspirin and acetaminophen are often effective to alleviate mildmuscular headache pain. Codeine or other narcotic preparations,tranquilizers, and antidepressants are sometimes administered topatients experiencing more severe muscular headache pain. Unfortunately,many of these patients develop physical dependence on these agents andmust be followed closely because of a significant incidence ofaddiction.

[0049] Nonetheless, the musculature of the head, neck, jaw, or upperback is tense and tender in many or most patients afflicted with amuscular headache, and one or more trigger points, or muscle knots, areoften present. Cervical spine arthritis and temporomandibular jointdisorders may contribute to the development of a muscular headache.

[0050] Treatments which have been recommended for the treatment ofmuscular headaches include reassurance and psychological support,massage of the head and neck, application of hot and cold packs,transcutaneous electrical neural stimulation, physical support (e.g.,use of orthopedic pillows and the like), administration of aspirincompounds, acetaminophen compounds, non-steroidal anti-inflammatorydrugs, tricyclic antidepressants, narcotic analgesics, oral musclerelaxants, with or without tranquilizers, muscle relaxants, and otheranalgesic compounds. These treatments are generally effective foralleviating mild- to moderate-intensity acute muscular headaches.

[0051] Some patients afflicted with either severe or chronic muscularheadaches sometimes experience relief from their acute symptoms usingthese known treatments. However, many do not. Furthermore, over time,many patients who initially respond to one or more of these therapiesbecome less responsive to these therapies, possibly because they developa tolerance to known medications, or because the disease processprogresses or increases. Additionally, symptoms may be influenced bypsychological factors which may remain constant or worsen. The sideeffects which accompany administration of known medications aresignificant and may become more severe over time.

[0052] There remains a significant unmet need for effective compositionsand methods of treating muscular headaches, including inhibiting musclecontraction headaches and tension headaches. The present inventionprovides compositions and methods which satisfy this need.

[0053] Systemic Delivery of a Pharmaceutically Active Agent

[0054] Numerous pharmaceutically active agents are useful when deliveredsystemically to a human patient. Systemic delivery of such agents cansometimes be effected by oral administration of a composition comprisingthe agent. However, many pharmaceutically active agents are degraded by,or otherwise react with acids, proteins, or other agents located in, thehuman gastrointestinal tract or the human liver or circulatory system,with the result that the agent loses its pharmaceutical usefulness. Forthis reason, many pharmaceutically active agents may not practically beadministered by an oral route to achieve systemic delivery of the agent.In addition, gastrointestinal absorption of an orally administeredmedication may be impaired in a distressed patient, such as a patientexperiencing a migraine or any severe headache.

[0055] Pharmaceutically active agents intended for systemic delivery toa human may be administered via an intravenous route using well knownmethods. However, such methods cause discomfort to the patient and oftencan be performed only in conjunction with frequent or continuoussupervision by a medical professional.

[0056] Methods of topically administering compositions to a human tissueto achieve systemic delivery of a pharmaceutically active agent which isa component of the composition are known, including the use oftransdermal or transmucosal pastes, cremes, liquids, solids andsemisolids impregnated with the composition, and the like. Systemicdelivery of a pharmaceutically active agent effected by topicaladministration methods are limited by the ability of the agent todiffuse through the tissue to which the composition is applied to reachblood vessels where the agent is absorbed and taken up for systemicdelivery.

[0057] A significant, unmet need remains for compositions and methodswhich can be used to systemically deliver or to enhance systemicdelivery of a pharmaceutically active agent to a human and whichovercome the limitations of known systemic delivery compositions andmethods.

[0058] The present invention provides compositions and methods whichsatisfy the needs described herein.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0059]FIG. 1 is a diagram depicting a sagittal section of a portion of ahuman head, the section being just to the right of the nasal septum. Asection is cut away at the posterior portion of the nasal cavity toreveal the approximate placement of the sphenopalatine ganglion. Indiciaused in this Figure include 12 inferior concha, 14 lower lip, 16 middleconcha, 18 maxillary nerve, 20 superior concha, 22 sphenopalatineganglion, 24 tongue, 26 trigeminal nerve, 28 uvula, and 30 upper lip.

[0060]FIG. 2 is a bar graph which depicts the percentage of patients whoexhibited at least 50% reduction in pain intensity following dorsonasaladministration of ropivacaine using the intranasal spray methoddescribed herein (“Nasal spray”), using the intranasal drip methoddescribed herein (“Nasal drip”), or using the intranasal cotton swabmethod described herein (“Sat'd Swab”).

[0061]FIG. 3 is a graph which depicts the percentage of patients whoexhibited at least 50% reduction in pain intensity followingadministration of various pharmaceutically active agents. The responseof patients to whom a placebo was a placebo is indicated by filledcircles (; data from Maizels et al., 1996, J. Amer. Med. Assoc.276:319-321 and The Subcutaneous Sumatriptan International Study Group,1991, New Eng. J. Med. 325:316-321); the response of patients to whomsumatriptan was administered (as described in The SubcutaneousSumatriptan International Study Group, 1991, New Eng. J. Med.325:316-321) is indicated by filled squares; the response of patients towhom lidocaine was administered (as described in Maizels et al., 1996,J. Amer. Med. Assoc. 276:319-321) is indicated by filled triangles; theresponse of patients to whom ropivacaine was administered by nasal sprayas described herein in Example 1 is indicated by filled invertedtriangles; the response of patients to whom ropivacaine was administeredby cotton swab as described herein in Example 1 is indicated by filleddiamonds.

[0062]FIG. 4, comprising FIGS. 4A through 4N, is a series of drawingswhich depict dorsonasal delivery apparatus of the invention. FIG. 4A isa diagram of a sagittal section through the right nostril and the rightportion of the nasal cavity of a human, illustrating the approximateplacement of the body 100 of the dorsonasal delivery apparatus describedherein. Abbreviations used in this Figure include apex A of the nasalcavity, nostril N, superior concha SC, middle concha MC, and inferiorconcha IC. FIG. 4B is a diagram of a coronal section through the nose ofa human taken along lines 4B-4B of FIG. 4A, illustrating the approximateplacement of a dorsonasal delivery device of the invention in the nasalcavity. FIG. 4C is a diagram similar to FIG. 4B, but depicting analternate embodiment of a dorsonasal delivery device of the presentinvention. FIGS. 4D through 4I illustrate various embodiments of thedorsonasal delivery device of the invention, as described herein.Alternative orientations of the device, before (solid) and after(dashed) inflation of the balloon 110 thereof are shown in FIG. 4G.FIGS. 4J and 4K, respectively, are diagrams of left and right side viewsof a dual-lumen dorsonasal delivery device described herein. FIGS. 4L,4M, and 4N are other embodiments of the dorsonasal delivery devicedescribed herein. In FIG. 4M, the position of an absorbent portion 110is shown alternatively in an engorged, extended position (solid) and acompressed position (dashed). In FIG. 4N, the absorbent portion 110 istapered in order to facilitate withdrawal from the nasal cavity withminimal trauma.

[0063]FIG. 5 is a diagram of an anatomically adapted dorsonasal deliverynozzle of the invention. The nozzle depicted in this Figure is adaptedfor the left nostril of a human patient.

[0064]FIG. 6 is a diagram of the orientation between the outlet port ofthe anatomically adapted dorsonasal delivery nozzle of the invention asshown in FIG. 5 and the apex of the nasal cavity of a human. The anglephi is indicated.

[0065]FIG. 7, comprising FIGS. 7A, 7B, and 7C, is a trio of diagramsdepicting manually pressure-actuated drug delivery devices havingintranostril applicators. A prior art device is depicted in FIG. 7A, inwhich actuating pressure is applied approximately coaxially with thenostril. In the devices of the invention, as depicted in FIGS. 7B and7C, actuating pressure is not applied coaxially with the nostril.

BRIEF SUMMARY OF THE INVENTION

[0066] One aspect of the invention relates to a method of inhibiting acerebral neurovascular disorder (CNvD) in a human patient. This methodcomprises intranasally administering a long-acting local anestheticpharmaceutical composition to the patient in an amount effective toinhibit the CNvD. The CNvD may, for example, be selected from the groupconsisting of tinnitus, cerebrovascular spasm, seizure, a disordermanifested during or after and associated with an acute ischemic event,and a neurovascular headache. Preferably, the CNvD is a migraine, suchas an acute migraine episode.

[0067] According to this method, the long-acting local anestheticpharmaceutical composition comprises a pharmaceutically acceptablecarrier, at least one local anesthetic ingredient selected from thegroup consisting of a long-acting local anesthetic, a persistent localanesthetic, and a sustained release formulation of a local anesthetic,and may further comprise a compound selected from the group consistingof an anti-epileptic, phenytoin sodium, a serotonin receptor agonist, aserotonin subclass 5HT1F receptor agonist, LY334,370, a sesquiterpenelactone, parthanolide, Tanacetum parthenium, and an extract of Tanacetumparthenium.

[0068] The invention includes a method of inhibiting cephalicinflammation in a human patient. This method comprises anesthetizing anerve structure associated with the disorder in the patient for a periodeffective to inhibit the inflammation (e.g., at least about one or twohours). The nerve structure can be anesthetized by any method known inthe art or described herein. For example, the nerve structure can beanesthetized by performing acupuncture upon the nerve structure,applying an electrical potential to the nerve structure, applyingelectromagnetic radiation to the nerve structure, or administering along-acting local anesthetic pharmaceutical composition to the nervestructure. In one embodiment, cephalic inflammation is inhibited in thepatient by energizing a dorsonasally implanted electronic neuralstimulator.

[0069] The invention also relates to an intranasal drug delivery deviceor applicator. This device comprises a body having a shape whichconforms to the shape of the nasal cavity of a human. The body has aproximal end and a distal portion having a distal end. The distalportion of the body can be urged through a nostril of the human into theapex of the nasal cavity without injuring the human. The distal end ofthe body may be rounded. The body may, for example, be substantiallyrigid, be flexible, or comprise a flexible portion.

[0070] Optionally, a lumen extends longitudinally within the body of theintranasal drug delivery device or applicator of the invention. Thelumen extends from the proximal end thereof to an outlet port at theexterior surface of the body, such as an outlet port on the distalportion of the body. The lumen may extend to a plurality of outletports, or a plurality of lumens may extend longitudinally within thebody from the proximal end thereof to a separate outlet port.Preferably, at least one outlet port is situated on the distal portionof the body in an orientation such that when the distal portion of thebody is in the apex of the nasal cavity, the outlet port faces aposterior or superior portion of the nasal cavity, such as thesphenoethmoidal recess or the superior epithelial surface of the nasalcavity, so that directed intranasal delivery of the drug can beachieved.

[0071] The body of the intranasal drug delivery device of the inventionmay, for example, have an elongated shape selected from the groupconsisting of an angled shape and a curved shape. The longitudinal axisof the body at the distal end thereof forms an angle of about 90 toabout 170 degrees (preferably about 110 to about 160, and morepreferably about 120 to about 150 degrees) with the longitudinal axis ofthe body at the proximal end thereof.

[0072] In one embodiment of the intranasal drug delivery device of theinvention, the device further comprises an extendable instrumentsituated with a lumen thereof. The extendable instrument is extendablethrough the outlet port of the lumen. The extendible instrument may, forexample, be selected from the group consisting of a swab, a rosette, aninflatable balloon, and a needle. The needle may be hollow, have aoutlet in its distal end, extend through the lumen, or have a proximalend connectable to a reservoir, such as one selected from the groupconsisting of a compressible reservoir, a deformable bulb, and asyringe.

[0073] In another embodiment of the intranasal drug delivery device ofthe invention, the body of the device has an absorbent portion on thedistal portion thereof. In a separate embodiment, the device has a lumenwhich communicates at the proximal end of the body with the interior ofa reservoir containing a pharmaceutical composition, such as one whichcomprises a long-acting local anesthetic. The pharmaceutical compositionmay, for example, be delivered in a form selected from the groupconsisting of a liquid, a gel, a foam, a mousse, a powder, a dispersedpowder, an atomized liquid, an aerosol, and a liposomal preparation.

[0074] The invention also relates to a method of intranasally (e.g.,dorsonasally) administering a composition to a human patient. Thismethod comprises inserting an intranasal drug delivery device of theinvention into a nostril of the patient, urging the device through thenostril such that the distal end of the body is in the apex of the nasalcavity, and contacting a portion of the nasal epithelium (e.g., aportion overlying the SPG) with the composition on the portion of theexterior surface.

[0075] The invention further relates to another method of intranasallyadministering a composition to a human patient. This method comprisesinserting an intranasal drug delivery device of the invention having alumen extending therethrough into a nostril of the patient, urging thedevice through the nostril such that the distal portion of the body isin the apex of the nasal cavity, and providing the composition to aportion of the nasal epithelium by way of the lumen.

[0076] The invention relates to still another method of intranasallyadministering a composition to a human patient. This method comprisesinserting an intranasal drug delivery device of the invention having alumen extending therethrough into a nostril of the patient, urging thedevice through the nostril such that the distal portion of the body isin the apex of the nasal cavity, urging an elongate instrumentcomprising the composition through the lumen (e.g., into the apex of thenasal cavity). The elongate instrument may, for example, be selectedfrom the group consisting of an extendable instrument comprising thecomposition, a swab impregnated with the composition, a rosetteimpregnated with the composition, a needle coated with the composition,an inflatable instrument comprising the composition, a balloon coatedwith the composition, a balloon impregnated with the composition, ahollow instrument having a lumen for providing the composition, and ahollow needle having a lumen for providing the composition, whereby thecomposition is provided to a portion of the nasal epithelium.

[0077] The invention also relates to an anatomically adapted intranasal(e.g., dorsonasal) delivery nozzle for intranasally administering acomposition to a human patient. The nozzle comprises a body having adelivery lumen extending therethrough from a proximal end of the body toan outlet port at a distal portion of the body and an exterior portion.The exterior portion has (i) a flattened portion situated peripherallybetween the proximal end and the distal portion for seating the nozzleagainst the nasal septum of the patient, (ii) an anterior portionsituated peripherally between the proximal end and the distal portionfor seating the nozzle against a portion of the external nasal cartilageof the patient, and (iii) an indented portion situated peripherallybetween the proximal end and the distal portion for seating the nozzleagainst a nasal concha of the patient. When the nozzle is seated, theoutlet port is situated within the nasal cavity of the patient such thatthe axis extending through the discharge port is offset from the apex ofthe nasal cavity by no more than about 30 degrees, and preferably by nomore than about 15 degrees. In an alternate embodiment, the bodycomprises a distal seating portion for seating the nozzle against thesuperior surface of the nasal cavity.

[0078] The body of the nozzle of the invention may, for example, bedeformable. For example, the body may be deformable at a certaincondition, but less deformable at a different condition. The nozzle maythus be adapted to the nasal cavity of the patient at the certaincondition and thereafter used at the different condition. By way ofexample, the body may be adapted to the nasal cavity of the patient at atemperature at which the body is deformable, and thereafter used at atemperature at which the body is less deformable.

[0079] The invention also relates to a method of intranasally (e.g.,dorsonasally) administering a composition to a human patient. Thismethod comprises seating within the nasal cavity of the patient ananatomically adapted intranasal delivery nozzle of the invention andthereafter providing the composition to the delivery lumen of thenozzle. The composition is thereby intranasally administered to thepatient.

[0080] The invention further includes an improved manuallypressure-actuated drug delivery device. The device comprises a bodyhaving an intranostril applicator for insertion into a nostril of apatient, a drug container, and a manually pressure-actuated actuatorfixed to at least one of the applicator and the container and actuatablyfluidly connecting the applicator and the container. Drug from thecontainer is provided to the applicator upon application of pressure bythe patient to the connector. The improvement comprises the actuatorbeing positioned with respect to the intranostril applicator in such away that actuating pressure must be applied to the actuator in adirection which is not co-linear with the axis of the nostril into whichthe applicator is inserted. Alternatively, the actuator may bepositioned with respect to the intranostril applicator in such a waythat actuating pressure must be applied to the actuator in a directionwhich is not parallel to the axis of the nostril. As another alternativeembodiment, the actuator may be positioned in such a way that actuatingpressure must be applied to the actuator in a direction which is offsetby at least about 30 degrees (preferably by at least about 45 degrees,at least about 60 degrees, or about 90 degrees) from the axis of thenostril.

[0081] The invention further includes a systemic drug delivery device.This device comprises a body having a shape which conforms to the shapeof the nasal cavity of a human. The body has a proximal end and a distalportion which can be urged through a nostril of the human into the apexof the nasal cavity without injuring the human. The body also has anapplicator portion in the form of at least one of a portion on which thedrug is present, a portion to which the drug may be supplied, and alumen through which the drug may be delivered. The applicator portion isadapted for location in close anatomic proximity to a highlyvascularized portion of the nasal epithelium when the distal portion ofthe body is in the apex of the nasal cavity.

[0082] The invention still further includes an anatomically adaptedintranasal delivery nozzle for systemically administering a compositionto a human patient. This nozzle comprises a body having a delivery lumenextending therethrough from a proximal end of the body to an outletport, and an exterior portion. The exterior portion has (i) a flattenedportion situated peripherally between the proximal end and the distalportion for seating the nozzle against the nasal septum of the patient,(ii) an anterior portion situated peripherally between the proximal endand the distal portion for seating the nozzle against a portion of theexternal nasal cartilage of the patient, and (iii) an indented portionsituated peripherally between the proximal end and the distal portionfor seating the nozzle against a nasal concha of the patient. When thenozzle is seated, the outlet port is situated within the nasal cavity ofthe patient such that the axis extending from the discharge port extendsthrough a highly vascularized portion of the nasal epithelium.

[0083] The invention also includes a method of inhibiting a cerebralneurovascular disorder in a human patient. This method comprisesenergizing a dorsonasally implanted electronic neural stimulator.

[0084] The invention also includes local anesthetic compound having thechemical structure of formula (IV), wherein R is ethyl, phenyl, or C₅-C₈straight- or branched-chain alkyl, and R′ is 2,6-dimethylphenyl,thiophene, or 2,5-dimethylthiophene, and wherein R″ and R′″ are selectedsuch that either (i) each of R″ and R′″ is a straight-chain alkylwherein R″ and R′″ have a total of 4 to 6 carbon atoms, or (ii) R″ andR′″ together form a heteroalkyl ring having a total of 5 to 7 carbonatoms and a nitrogen atom

[0085] For example, the local anesthetic compound may have the structureof formula (III)

[0086] In the structures of formulas (III) and (IV), the carbon atomindicated by the asterisk is a chiral center.

[0087] The invention also relates to a kit comprising the long-actinglocal anesthetic pharmaceutical composition of the invention and anintranasal drug delivery device or applicator for administering thecomposition to the patient. For example, the device or applicator may beone of those described herein, and can be adapted for dorsonasaldelivery. The kit may also comprise instructional material whichdescribes intranasal or dorsonasal administration of the composition toa human or another animal.

DETAILED DESCRIPTION OF THE INVENTION

[0088] The first aspect of the present invention is based on thediscovery that intranasal administration of a long-acting localanesthetic pharmaceutical composition to a human patient experiencing acerebral neurovascular disorder (CNvD) inhibits the CNvD or a symptom ofthe CNvD. The invention also relates to the discovery that anesthesia ofa dorsonasal nerve structure (DnNS) in a human patient experiencing aCNvD inhibits the CNvD or a symptom of the CNvD if the anesthesiapersists for a period of at least about an hour, and preferably for aperiod of at least about two hours.

[0089] Local anesthetics are known to provide analgesia to a bodysurface to which they are applied. However, such analgesia persists onlyfor a period of time which is characteristic of the particular localanesthetic used and the site anesthetized. Local anesthetics may beroughly divided into classes based on the duration of analgesia providedto a patient following topical administration.

[0090] It is known that intranasal administration of a relativelyshorter-acting local anesthetics such as lidocaine or cocaine decreaseshead pain for a period approximately equal to the duration of analgesiawhich is characteristic of such shorter- acting local anesthetics.Lidocaine and cocaine each exhibit a duration of action shorter thanabout one hour when intranasally administered.

[0091] What was not known, and what represents a surprising discovery,is that intranasal, and preferably dorsonasal, administration of a localanesthetic preparation which either relieves a symptom of the CNvD forat least about one hour or exhibits a duration of anesthesia equal to atleast about one hour is effective both to relieve head pain beyond theperiod of expected anesthesia and, more importantly, to inhibit theCNvD, such that symptoms of the CNvD, including head pain, do notrebound following the period of anesthesia, or even for many hours,days, or weeks thereafter. Rebound remains a major shortcoming of priorart treatments. It has furthermore been discovered that cephalicinflammation, a condition associated with CNvDs (as a symptom, as acause, or both) can be inhibited by interrupting or interfering withneural transmission of neural impulses through one or more DnNSs, suchas by intranasally (and preferably dorsonasally) administering along-acting local anesthetic pharmaceutical composition to the patient,by applying an electrical potential to the DnNS, or by any otheranesthetic method described herein.

[0092] Prior art intranasal delivery devices (e.g., intra-nostrilsqueeze-type mist dispensers) typically deliver compositions to only thedistal portions of the nose, such as to portions of the nasal mucosawithin a few centimeters of the nares. Devices disclosed herein can beused to direct compositions to other portions of the nasal cavity,including to portions of the nasal epithelium that contact or overlieimportant physiological structures, such as nerves, other nervoustissues, and blood and lymphatic vessels in the superior and dorsalportions of the nasal cavity. The devices can also be used to targetparticular structures.

[0093] Definitions

[0094] As used herein, the term “cerebral neurovascular disorder” (CNvD)means a disorder which is characterized by one or more disturbances inthe normal functioning of at least one component of the cerebralvascular or cerebral nervous system in a human. CNvDs which have beencharacterized include migraine, cluster headaches, other headaches ofneurovascular etiology, tinnitus, and cerebrovascular spasm. An “acute”CNvD means an individual episode of a CNvD. Thus, an acute CNvDincludes, but is not limited to, an acute neurovascular headacheepisode, a single episode of tinnitus, a single episode ofcerebrovascular spasm, and a set of symptoms or a disorder manifestedduring or after and associated with an acute ischemic event such as asingle cerebrovascular occlusion or a stroke.

[0095] As used herein, cephalic inflammation includes, but is notlimited to, cerebral inflammation, meningeal inflammation, and othervarieties of extracranial and intracranial inflammation.

[0096] As used herein, a CNvD or an acute CNvD or a muscular headache is“inhibited” if at least one symptom of an episode of the CNvD or themuscular headache is alleviated, terminated, or prevented. As usedherein, a CNvD or muscular headache is also “inhibited” if the frequencyof recurrence, the severity, or both, of acute CNvD or muscular headacheis reduced.

[0097] As used herein, the term “muscular headache” means head, neck,face, periocular, scalp, or upper back pain associated with contractionof muscles of the head, neck, jaw, or upper back of a patient. The headpain may be experienced in or around a muscle, or it may be referred toa part of the head or upper back distinct from the site of the affectedmuscle. It is understood that the term “muscular headache” includes bothacute and chronic episodes of head pain. By way of example, muscularheadaches include muscle contraction headaches and tension headaches.

[0098] As used herein, a CNvD or a muscular headache is “terminated” ifat least one symptom of the CNvD or muscular headache ceases in apatient and the patient does not experience the symptom for at leastseveral hours or, preferably, for at least about one day.

[0099] As used herein, a “recurring” CNvD is a CNvD which is experiencedby a patient more than once in a six-month period.

[0100] As used herein, the term “acute ischemic event” refers to asingle episode experienced by a human patient wherein a tissue of thepatient is insufficiently supplied with oxygen. Acute ischemic eventsinclude, for example, ischemia associated with a stroke, ischemiaassociated with vasospasm, and ischemia associated with an acuteneurovascular headache episode.

[0101] As used herein, the term “neurovascular headache” means aheadache of neurovascular etiology associated with a disease, disorder,or imbalance of the nervous or vascular systems in a human. Headaches ofneurovascular etiology include, but are not limited to, migraines andcluster headaches.

[0102] As used herein, the term “acute neurovascular headache episode”means a single neurovascular muscular headache which either has aduration greater than about one hour or recurs more than once in aone-day period in a human patient. Examples of acute neurovascularheadache episodes include, but are not limited to, a single persistentneurovascular headache, an acute migraine episode, each of theindividual headache episodes associated with a recurrent neurovascularheadache, and each of the individual headache episodes associated with acluster headache.

[0103] As used herein, the term “acute muscular headache episode” meansa single muscular headache. Examples of acute neurovascular headacheepisodes include, but are not limited to, a single muscle contractionheadache and a single tension headache.

[0104] As used herein, the term “chronic muscular headache” means amuscular headache muscular which is experienced by a human patient morethan fifteen days per month for a period of at least about six months.

[0105] As used herein, the term “persistent neurovascular headache”means a headache of neurovascular etiology which persists for a periodlonger than about one hour.

[0106] As used herein, the term “recurrent neurovascular headache” meansa headache of neurovascular etiology which is experienced by a humanpatient more than once in a one-day period.

[0107] As used herein, the term “rebound” of a CNvD means experience bya patient of one or more symptoms of the CNvD following a period duringwhich the patient did not experience the one or more symptoms, thesymptom-free period having been preceded by an earlier period duringwhich the patient experienced one or more symptoms of the CNvD. It isunderstood that it is not always possible to discern whether a patientwho did not experience the one or more symptoms for a period isafflicted with the same episode or with a separate episode of the sameCNvD. Thus, the term is inclusive of both situations.

[0108] As used herein, the term “migraine” means a human disordercharacterized by at least one persistent neurovascular headache episode.

[0109] As used herein, the term “an acute migraine episode” means anindividual headache experienced by a human patient afflicted withmigraine.

[0110] As used herein, the term “cluster headache” means a humandisorder characterized by recurrent neurovascular headaches of shortduration.

[0111] As used herein, the term “individual headache episode associatedwith a cluster headache” means a single neurovascular headacheexperienced by a human patient afflicted with cluster headache.

[0112] As used herein, the term “prodromal headache symptom” means asymptom which is experienced by a patient and which is associated withthe onset or indicates the imminent onset of an acute neurovascularheadache episode.

[0113] As used herein, a “nerve structure” means a nerve, a plurality ofnerves located in close anatomic proximity to one another, or aganglion.

[0114] As used herein, a nerve structure is “associated with” a CNvD if,when the nerve structure is anesthetized in a human patient afflictedwith the disorder, the patient experiences relief from at least onesymptom of the CNvD.

[0115] As used herein, a “dorsonasal nerve structure” (DnNS) means thesphenopalatine ganglion (SPG) or a nerve structure located in closeanatomic proximity to the SPG.

[0116] As used herein, a first nerve structure is located in “closeanatomic proximity” to a second nerve structure if the second nervestructure is anesthetized following anesthesia of the first nervestructure effected by administration of a local anesthetic to a tissuewhich comprises or overlies the first nerve structure. It is believedthat dorsonasal administration of a local anesthetic anesthetizes atleast one, and perhaps all, of the SPG, the cavernous sinus ganglion,the carotic sinus ganglion, numerous branches of the maxillary nerve,the ethmoidal nerve, the ethmoidal ganglion, and the vidian nerve. Thus,by way of example, each of the cavernous sinus ganglion, the caroticsinus ganglion, numerous branches of the maxillary nerve, the ethmoidalnerve, the ethmoidal ganglion, and the vidian nerve is located in closeanatomic proximity to the SPG, and thus each is a DnNS.

[0117] As used herein, an “intranasal nerve structure” (“InNS”) is anerve structure that contacts the nasal epithelium or lies insufficiently close proximity to the nasal epithelium that a compoundapplied to the epithelium is able to diffuse to or otherwise gain accessto the nerve structure.

[0118] As used herein, an “intranasal blood vessel” (InBV”) is a bloodor lymphatic vessel that contacts the nasal epithelium or lies insufficiently close proximity to the nasal epithelium that a compoundapplied to the epithelium is able to diffuse to or otherwise gain accessto the blood vessel.

[0119] As used herein, a nerve structure is “anesthetized” when thecapacity of the ganglion to generate or conduct nerve impulses issignificantly impaired, relative to the capacity of the nerve structureto generate or conduct nerve impulses in the absence of intervention,such as by administration of a local anesthetic. Anesthesia of the SPGeffected by administration of a local anesthetic, for example,interrupts the functioning normally associated with the SPG and withother DnNSs. It is understood that anesthesia of a nerve structure maybe achieved not only using a local anesthetic, but also by anyanesthetic method as set forth herein.

[0120] As used herein, the capacity of a DnNS to generate or conductnerve impulses is “significantly impaired” when that capacity is reducedby an amount sufficient to relieve the pain associated with a headacheof neurovascular origin in a patient afflicted with such a headache.

[0121] As used herein, the term “shorter-acting local anesthetic” meansa local anesthetic which, when intranasally administered to a humanpatient experiencing a CNvD or a muscular headache, relieves at leastone symptom of the CNvD or muscular headache for a period of less thanabout one hour. By way of example, lidocaine and cocaine areshorter-acting local anesthetics.

[0122] As used herein, the term “long-acting local anesthetic” means alocal anesthetic which, when intranasally administered to a humanpatient experiencing a CNvD or a muscular headache, reliably orconsistently relieves at least one symptom of the CNvD or muscularheadache for a period of at least about one hour. By way of non-limitingexamples, bupivacaine and ropivacaine are long-acting local anesthetics.

[0123] As used herein, the term “persistent local anesthetic” means alocal anesthetic which, when intranasally administered to a humanpatient experiencing a CNvD or a muscular headache, relieves at leastone symptom of the CNvD or muscular headache for a period of at leastabout two hours.

[0124] As used herein, the terms “vasoconstrictor” and “vasoconstrictingagent” are used interchangeably to mean an agent which inducesdiminution of the lumenal caliber of a blood vessel. The agent may be achemical compound or a stimulus applied to a motor neuron which causesvasoconstriction. Hence, administration of a vasoconstrictor maycomprise administration of a chemical compound, application of such astimulus, or both. Vasoconstrictors include, but are not limited to,epinephrine, norepinephrine, and phenylephrine.

[0125] As used herein, the terms “vasodilator” and “vasodilating agent”are used interchangeably to mean an agent which induces an increase inthe lumenal caliber of a blood vessel.

[0126] As used herein, the term “intranasal administration” of acomposition and grammatical forms thereof mean delivery of thecomposition to any portion of the nasal epithelium.

[0127] As used herein, the term “dorsonasal administration” of acomposition and grammatical forms thereof mean delivery of thecomposition to a tissue, fluid, or surface of a human, whereby acomponent of the composition is provided to a DnNS or to a tissueoverlying a DnNS. Dorsonasal administration may be accomplished, forexample, by topical administration of the composition to the region ofthe nasal epithelium overlying the SPG or to the surface of the nasalepithelium near the region of the nasal epithelium overlying the SPG,whereby a component of the composition is capable of diffusing throughany tissue or fluid which may be interposed between the surface and theSPG. Such administration may also be accomplished, for example, byinjecting the composition directly into the SPG or by injecting thecomposition into or otherwise administering the composition to a tissueor fluid near the SPG, whereby a component of the composition is capableof diffusing through any tissue or fluid which may be interposed betweenthe site of injection or administration and the SPG.

[0128] As used herein, the term “the region of the nasal epitheliumoverlying the SPG” means the area of the nasal epithelium having ageometrical relationship with the SPG whereby an imaginary lineapproximately perpendicular to the surface of the epithelium andextending from the surface of the epithelium in the direction of thebasement membrane of the epithelium passes through a DnNS.

[0129] As used herein, the term “the surface of the nasal epitheliumnear the region of the nasal epithelium overlying the SPG” means aportion of the surface of the nasal epithelium which is continuous withand sufficiently geometrically close to the region of the nasalepithelium overlying the SPG such that a compound applied anywhere onthis surface is able to diffuse to the SPG. It is understood that theboundaries of the surface are dependent upon the diffusivity of thecompound in the epithelium and in any tissue or fluid situated betweenthe epithelium and the SPG. Thus, the area of this surface will begreater for a compound having high diffusivity than the areacorresponding to a compound having a lower diffusivity. It is furtherunderstood that, where the compound has a half-life in vivo, theboundaries of “the surface of the nasal epithelium near the region ofthe epithelium overlying the SPG” are dependent upon the half-life ofthe compound. Thus, the area of this surface will be greater for acompound having a longer half-life than the area corresponding to acompound having a shorter half-life.

[0130] In the case of a compound having a diffusivity and a half-lifecomparable to that of ropivacaine, “the surface of the nasal epitheliumnear the region of the epithelium overlying the SPG” includes, but isnot limited to, the surface of the region of the nasal epitheliumoverlying the SPG and the surface of the nasal epithelium continuouswith and located within about three centimeters of that region.Preferably, such a compound is delivered to the surface of the nasalepithelium within about two centimeters of that region, and even morepreferably to the surface of the nasal epithelium within about onecentimeter of that region. Most preferably, the compound is delivered tothe surface of the nasal epithelium overlying the SPG. It is understoodthat, in the case of a local anesthetic such as ropivacaine, the surfaceincludes the epithelial surface covering the dorsal surface of the nasalcavity extending caudally from approximately the superior extent of thesphenoethmoidal recess to approximately the inferior boundary of thenasopharynx and extending laterally between the region of the surfacecovering the perpendicular plate of the right palatine bone and theregion of the surface covering the perpendicular plate of the ethmoidbone and between the region of the surface covering the perpendicularplate of the left palatine bone and the region of the surface coveringthe perpendicular plate of the ethmoid bone.

[0131] As used herein, the “superior portion” of the nasal epitheliummeans one or more areas of the nasal epithelium situated on or above thesuperior face of the superior conchae.

[0132] As used herein, the term “non-intravenous administration” of acomposition means administration of the composition by any means otherthan injection or infusion of the composition directly into thebloodstream of a human patient.

[0133] As used herein, the term “long-acting local anestheticpharmaceutical composition” means a chemical composition comprising apharmaceutically acceptable carrier and at least one local anestheticingredient selected from the group consisting of a long-acting localanesthetic, a persistent local anesthetic, and a sustained releaseformulation of a local anesthetic, wherein administration of thecomposition to a patient experiencing a CNvD or muscular headacheinhibits the CNvD or muscular headache.

[0134] As used herein, the term “pharmaceutically acceptable carrier”means a chemical composition with which a local anesthetic may becombined and which, following the combination, can be used to administerthe local anesthetic to a human patient without significantly adverselyaffecting the patient.

[0135] As used herein, “a sustained release formulation of a localanesthetic” is a pharmaceutical composition comprising a localanesthetic, wherein upon administration of the composition to a tissueof a human patient, the local anesthetic is delivered to the tissue on acontinuous or semi-continuous basis for a period of hours, days, orweeks. Methods of making and using sustained release formulations oflocal anesthetics are well within the skill of one of ordinary skill inthe art of pharmacology. In addition, inclusion of a vasoconstrictor inthe composition may prolong the duration of the anesthetic effect.

[0136] As used herein, a composition is “formulated for intranasaldelivery” if the composition is susceptible of intranasal administrationto a human and if the composition is not significantly injurious to thetissues lining the nasal cavity of a human.

[0137] As used herein, the term “pharmaceutically active agent” means acomposition which, when administered to a human patient, has abiochemical or physiological effect on the patient.

[0138] As used herein, “instructional material” includes a publication,a sound, video, or other recording, a diagram, or any other medium ofexpression which can be used to communicate the usefulness of thecomposition of the invention for inhibiting a CNvD or a muscularheadache. The instructional material of the kit of the invention may,for example, be separate from, included with, or affixed to a containerwhich contains the composition of the invention or be shipped togetherwith a container which contains the composition. The instructionalmaterial may, for example, describe an appropriate dose of thecomposition of the invention or directions for using an applicatorincluded in the kit to intranasally or dorsonasally administer a localanesthetic.

[0139] As used herein, a “eutectic mixture” is a mixture comprising atleast one local anesthetic and at least one eutectic ingredient.

[0140] As used herein, a “eutectic ingredient” is a chemical compoundwhich, when mixed with a local anesthetic, yields a mixture having amelting point lower than the melting point of the local anesthetic.

[0141] As used herein, a body has a shape which “conforms to” the nasalcavity of a human if the shape of the elongate body is, or becomes uponinsertion into the nasal cavity, similar to the shape of the nasalcavity.

[0142] Description of the Invention

[0143] Inhibition of a Cerebral Neurovascular Disorder

[0144] One aspect of the invention is based on the discovery thatintranasal, and preferably dorsonasal administration of a long-actinglocal anesthetic pharmaceutical composition to a human patientexperiencing a cerebral neurovascular disorder (CNvD) inhibits the CNvD.The long-acting local anesthetic pharmaceutical composition comprises alocal anesthetic ingredient selected from the group consisting of along-acting local anesthetic, a persistent local anesthetic, and asustained release formulation of a local anesthetic. The duration ofrelief from a symptom of a CNvD effected by intranasal administration ofthe long-acting local anesthetic pharmaceutical composition according tothis method is at least about one hour, and is preferably at least abouttwo hours. However, the duration may be at least about seventy-five,ninety, one hundred and five, or any other number of minutes such thatthe effective duration of relief is greater than that effected byintranasal administration of either lidocaine or cocaine. Inhibition ofa CNvD may include inhibition of one or more symptoms or aspects of theCNvD. By way of example, inhibition of a CNvD includes inhibition ofcephalic inflammation associated with the CNvD.

[0145] Intranasal, and preferably dorsonasal, administration of at leastone long-acting or persistent local anesthetic, such as bupivacaine orropivacaine, to a human patient experiencing a CNvD is sufficient toinhibit the CNvD or a symptom of the CNvD. Furthermore, intranasal ordorsonasal administration of a composition comprising a sustainedrelease formulation of a shorter-acting local anesthetic inhibits theCNvD or a symptom thereof. By way of example, the CNvD may be aneurovascular headache, tinnitus which does not accompany aneurovascular headache, a cerebrovascular spasm which does not accompanya neurovascular headache, or an acute CNvD.

[0146] Symptoms of an acute neurovascular headache episode which can beinhibited by intranasal or dorsonasal administration of a long-actinglocal anesthetic pharmaceutical composition include, but are not limitedto, head pain, cephalic inflammation (e.g., cerebral inflammation,meningeal inflammation, and inflammation of the hypothalamus or otherportions of the brain), tinnitus, visual changes, phonophobia,photophobia, nausea, seizure, cerebrovascular spasm, symptoms of acuteischemic events, such as muscle weakness, dysphasia, dysphonia,cognitive impairment, autonomic imbalances, and the like.

[0147] Prior art methods of treating an acute CNvD often transientlyand/or incompletely relieve head pain, the primary symptom of manyCNvDs. In contrast, the compositions, kits, and methods of the presentinvention provide lasting and effective relief of the symptoms of aCNvD. Without wishing to be bound by any particular theory, it isbelieved that intranasal administration of a long-acting localanesthetic pharmaceutical composition to a patient experiencing a CNvDprovides relief by inhibiting the physiological processes underlying theCNvD, whereby both the CNvD and symptoms of the acute CNvD areinhibited.

[0148] Prevention of an Acute Cerebral Neurovascular Disorder

[0149] The method described herein for inhibiting an acute CNvD includesa method of preventing a CNvD, including a method of preventing one ormore symptoms (e.g., cephalic inflammation) associated therewith.Certain CNvDs, particularly migraines, are associated with prodromalsymptoms which are experienced by a patient prior to the onset of thedisorder. By treating a patient using the method described herein forinhibiting a CNvD at a time when the CNvD is expected or at a time whena prodromal symptom of the CNvD is experienced by the patient, the CNvDmay be prevented.

[0150] Decreasing the Frequency and/or Severity of Recurring CNvDs

[0151] Numerous cerebral CNvDs including, but not limited to migrainesand TIAs, are characterized by periodic or irregular recurrence. Overtime, severity of CNvDs often seems to increase and many CNvD-afflictedpatients seem to experience CNvD episodes more frequently. It wasobserved that the frequency of recurrence and severity of CNvD episodesdecreased with time in patients using the compositions and methodsdescribed in the present disclosure, even after treatment was no longeradministered. These phenomena have not been previously observed with anyother CNvD treatment method, including any migraine treatment method.The compositions, kits, apparatus, and methods of the invention areuseful for decreasing the frequency of recurrence, the severity, orboth, of CNvD episodes experienced by a patient afflicted with recurringCNvDs such as migraines and TIAs.

[0152] The invention thus includes a method of decreasing the frequencyor severity with which CNvD episodes are experienced by a patientafflicted with a recurring CNvD. The method comprises intranasally, andpreferably dorsonasally, administering to a patient experiencing a CNvDepisode a long-acting local anesthetic pharmaceutical composition. Thecomposition comprises a local anesthetic which is preferably along-acting local anesthetic, a persistent local anesthetic, or asustained release formulation of a shorter-acting or a long acting or apersistent local anesthetic, and is preferably administered to thepatient early in the course of the CNvD episode. Preferably, the localanesthetic is administered to the patient within two hours following theonset of the episode, more preferably within one hour, and even morepreferably within thirty minutes of the onset. Early administrationprovides more prompt relief, but administration of the local anestheticaccording to this invention may be at any time with good results.

[0153] Other Acute Cerebral Neurovascular Disorders

[0154] Intranasal, and preferably dorsonasal, administration of a localanesthetic can also be used to treat any CNvD, in addition to migrainesor other neurovascular headaches. Examples of acute CNvDs other thanacute neurovascular headache episodes include, but are not limited to,tinnitus, seizures or seizure-like activities, cerebrovascular spasm,cephalic (e.g., meningeal) inflammation, and disorders manifested afterand associated with an acute ischemic event such as a stroke, reversibleischemic neurological deficit, or transient ischemic attack. The localanesthetic compounds, formulations, dosages, and methods ofadministration which are useful for inhibiting these CNvDs aresubstantially the same as those described herein with respect toinhibiting a neurovascular headache. Where the acute CNvD is associatedwith cerebral ischemia, the amount of brain tissue which experiencesischemic damage may be reduced by this method.

[0155] Stimulation of DnNSs such as the trigeminal nerve can inducerelease from the DnNS of peptides and other neurotransmitters andhumoral factors such as nitric oxide. Some of these neurotransmittersand humoral factors resemble (or are identical to) compounds releasedfrom injured, hyper-stimulated, or growing nerves. These compounds caninduce meningeal inflammation, and can, over time, induce anatomic andphysiologic changes which facilitate pathways that allow more efficienttransmission of nociceptive impulses and that lower triggeringthresholds. Thus, if release or endurance of these compounds in thevicinity of the DnNS is not minimized, the DnNS can becomehypersensitized, with the result that the CNvD recurs more frequently orreadily. Release of compounds which induce meningeal inflammation can beminimized, as described herein, by anesthetizing the DnNS for aneffective period of at least about one hour, and preferably two hours.Release of such compounds may also be minimized by providing a serotonin(5HT) agonist or another pharmaceutical agent to the DnNS, preferably inconjunction with the long-acting local anesthetic pharmaceuticalcomposition. These two agents may, for example, be administered in theform of a single pharmaceutical composition comprising both along-acting local anesthetic composition and a 5HT agonist (e.g.,sumatriptan, zolmitriptan, rizatriptan, or naratriptan), or in the formof two separate pharmaceutical compositions (e.g., an intra- ordorsonasally administered long-acting local anesthetic pharmaceuticalcomposition and an oral 5HT agonist) having overlapping periods ofbiological effect. When the 5HT agonist is administered locally (e.g.,dorsonasally) to the DnNS, onset time of the pharmacological effect ofthe agonist may be reduced and duration of the pharmacological effect ofthe agonist may be extended by administering the agonist in conjunctionwith a vasoconstrictor. Furthermore, uptake of the 5HT agonist may befurther improved by including the R-enantiomer of the local anesthetic(e.g., R-bupivacaine or a mixture of the R- and L-enantiomers ofbupivacaine, such as a mixture wherein about 5-30% of bupivacaine isR-bupivacaine) in the composition. An optimum concentration may be used,wherein a more effective, powerful, and prolonged nerve block can beobtained, while also allowing increased uptake of any co-administeredpharmaceutical agent.

[0156] The local anesthetic compounds, formulations, dosages, andmethods of administration which are useful for inhibiting these CNvDsare substantially the same as those described herein with respect toinhibiting a neurovascular headache. Where the acute CNvD is associatedwith cerebral ischemia, the amount of brain tissue which experiencesischemic damage may be reduced by this method.

[0157] Tinnitus, cephalic inflammation, and these other CNvDs may alsobe inhibited by anesthetizing a DnNS using alternate anesthetic methodsincluding, but not limited to, transcutaneous electrical neuralstimulation, electromagnetic techniques, application of radio frequencyradiation, and surgical intervention to sever or disrupt the DnNS.

[0158] Duration of Anesthetic Effect

[0159] It has been discovered that intranasal administration of along-acting local anesthetic pharmaceutical composition is necessary inorder to inhibit a CNvD in a human patient. That is, intranasaladministration of relatively shorter-acting local anestheticcompositions, such as a lidocaine-containing composition which is not asustained release formulation, provides only transient relief (i.e.,less than about one hour) from CNvD symptoms, without inhibiting theCNvD.

[0160] It is preferable that the long-acting local anestheticpharmaceutical composition of the invention, when administeredintranasally, and preferably dorsonasally to a patient experiencing aCNvD, inhibits at least one symptom of the CNvD for a period of at leastabout one hour. Thus, as described herein, compositions comprisingbupivacaine or ropivacaine are effective for inhibiting a CNvD whenadministered intranasally to a patient, while compositions comprisinglidocaine in a non-sustained release formulation are not effective forinhibiting a CNvD. Thus, the long-acting local anesthetic pharmaceuticalcomposition preferably comprises a local anesthetic ingredient whichrelieves at least one symptom of a CNvD for a period greater than theperiod of relief provided by intranasal administration of lidocaine, andmore preferably relieves the symptom for at least about as long asropivacaine.

[0161] It is believed that anesthesia of a DnNS for a period of at leastabout one hour, or preferably at least about two hours, results ininhibition of both the symptoms and the physiological processes of aCNvD, including sterile inflammation and vascular lability, associatedwith neurovascular headache episodes such as migraines and clusterheadaches. Thus, for example, a migraine and its accompanying symptomsmay be inhibited by intranasally, and preferably dorsonasally,administering a long-acting local anesthetic, a persistent localanesthetic, or a sustained release formulation of a local anesthetic toa patient experiencing the migraine and its symptoms. Preferably, theperiod is one which is effective to terminate these processes, wherebyboth the processes and the symptoms associated with the CNvD areterminated.

[0162] At least one investigator (Barre, 1982, Headache 22:69-73) hasinvestigated the use of cocaine, a toxic, addictive, shorter-actinglocal anesthetic with well-known potent central nervous systemproperties, to relieve the pain associated with an individual headacheepisode associated with a cluster headache.

[0163] The addictive, toxic, and central nervous system excitatoryqualities of cocaine render it an inappropriate treatment in virtuallyall current clinical settings. Hence, it is preferable that the localanesthetic used in the method of the invention be a local anestheticother than cocaine. Thus, it is preferred to use a long-acting localanesthetic, a persistent local anesthetic, or a sustained release formof a shorter-acting local anesthetic other than cocaine in the methodsof the invention.

[0164] Prior art investigations have examined the effectiveness oflidocaine, a shorter- acting local anesthetic, for providing relief fromheadaches of neurovascular origin (Kittrelle et al., 1985, Arch. Neurol.42:496-498; Kudrow et al., 1995, Headache, 35:79-82; Maizels et al.,1996, J. Amer. Med. Assoc. 276:319-321). These investigations involvedintranasal administration of 4% (w/v) lidocaine, wherein the doses weresometimes repeated. Although many patients in these studies experienceda short term decrease in head pain, a significant number of thesepatients required supplemental medication with other known headachetherapeutic agents and the rate of rebound was high.

[0165] Not recognized by these investigators was the fact that theirinvestigations were hampered by the incapacity of lidocaine to provideconsistent, long-lasting relief from the CNvD for a period of at leastabout one hour. Hence, although intranasal administration of highconcentrations of lidocaine provided short term pain reduction, theacute neurovascular headaches experienced by the patients worsened orrebounded when the anesthetic effects of lidocaine subsided, withinabout an hour. Any effect which long-acting local anesthetics might havehad upon inhibiting acute neurovascular headache episodes in thepatients involved in those investigations was not recognized. The factthat no further development of lidocaine or its derivatives as theprimary pharmaceutically active agent for persistent or recurringneurovascular headache relief was pursued, despite the critical need forsuch agents, is further evidence that the importance of the period ofinhibition of at least one symptom of the CNvD, such as a period on theorder of at least about one hour, and preferably at least about twohours, was not recognized as being useful to abort the physiologicpathology of sterile inflammation and vasomotor instability which, whennot aborted, triggers another headache episode upon subsidence of theanesthetic effect of the shorter-acting local anesthetic.

[0166] The results of studies by Kudrow et al. (1995, Headache,35:79-82), Maizels et al. (1996, J. Amer. Med. Assoc. 276:319-321), andBarre (1982, Headache 22:69-73) can be explained by the model of CNvDspresented herein, wherein a DnNS such as the SPG is involved in thepathogenesis of headaches of neurovascular etiology. None of these priorart studies recognized that the severely limited effectiveness ofintranasal administration of either lidocaine or cocaine for thealleviation of pain associated with a headache of neurovascular etiologywas due to the fact that lidocaine and cocaine are merely shorter-actinglocal anesthetics when used in this manner. Indeed, repeat doses ofcocaine and lidocaine were needed to treat individual and subsequentshort duration headache episodes associated with a cluster headache.

[0167] Inhibition of a CNvD such as an neurovascular headache requiresintranasal, and preferably dorsonasal, administration of a long-actinglocal anesthetic pharmaceutical composition which provides relief from asymptom of the CNvD for a period longer than that effected by thetreatments in the investigations of Kudrow et al., Maizels et al., andBarre, namely for a period of at least about one hour, and preferably atleast about two hours.

[0168] Shorter-acting local anesthetics are not consistently or reliablyeffective for inhibiting a CNvD when administered in a single dose or inmultiple doses administered over a short period of time such as a fewminutes. Nonetheless, using the teachings of the present invention, itis possible to use shorter-acting local anesthetics in a manner moreeffective to inhibit a CNvD without causing the side effects associatedwith repetitive dosing of these agents at high concentration. In orderto inhibit a CNvD, it is necessary that a shorter-acting localanesthetic be intranasally, and preferably dorsonasally, administered asa sustained release formulation, or that an additional compound whichextends the duration of anesthesia effected by the shorter-acting localanesthetic, such as epinephrine or another vasoconstrictor, beco-administered to the patient. Preferably the additional compound isadministered to the patient in a composition comprising the localanesthetic and the additional compound. Compounds, formulations, anddosages of the vasoconstrictors described in this method are known inthe art. For example, vasoconstrictive compositions may be used atart-recognized effective doses, such as, about 0.001 milligram permilliliter to about 0.01 milligram per milliliter of epinephrine.Similarly, the other additional compounds described in this paragraphmay be used at art-recognized effective doses.

[0169] Theory Proposed to Explain the Efficacy of the Compositions andMethods of the Invention for Inhibiting a Neurovascular Headache

[0170] It should be appreciated that the superiority of the compositionsand methods of the invention relative to the compositions and methods ofthe prior art does not depend upon the accuracy of the theory offered toexplain the superior results.

[0171] While not wishing to be bound by any particular theory ofoperation, it is believed that intranasal administration of thecomposition of the present invention inhibits a neurovascular headacheby anesthetizing a dorsonasal nerve structure (DnNS) in the patient fora period effective to inhibit the physiological processes that result inthe neurovascular headache, such as a period on the order of at leastabout an hour, and preferably at least about two hours.

[0172] Still without wishing to be bound by any particular theory, it isbelieved that the following model explains the physiological processesunderlying an acute neurovascular headache. An acute neurovascularheadache generation center (ANvHGC) is located in the pons of the humanbrain, near the locus coeruleus. The ANvHGC initiates an excitatorysignal which affects the reticular formation, the trigeminal nerve, andsympathetic, parasympathetic, and other outflows from the midbrain andpons. Trigeminal nerve fibers innervate cerebral blood vessels andmodulate vasomotor function and intra- and extracranial blood vesseltone and communicate with multiple neural structures. Stimulation of thetrigeminal nerve by the ANvHGC results in changes in efferent andafferent neural activity and changes in regional intracranial bloodflow. Many factors, including stimulation of the trigeminal nerve by theANvHGC, facilitate neurogenic inflammation and associated vasomotor andother changes, including, but not limited to, monocytic and lymphocyticinfiltrates, perivascular edema, and release of neurohumoral and otherchemical factors. This results in intra-and extracranial neural andvascular hyperexcitability. This hyperexcitability decreases thethreshold for neuronal and humoral signaling and other triggers whichinduce further vasospasm or further neuronal hyperexcitability andaltered efferent and afferent activity. Prolonged vasospasm leads totissue ischemia, which induces further release of neurohumoral factors,increases perivascular edema, and exacerbates neurogenic inflammation.These local neurovascular changes induce greater neuronal and vascularhyperexcitability. All of these factors contribute to thepathophysiologic cycle of neurovascular headache.

[0173] Altered cerebral blood flow, neurogenic inflammation, andassociated vasomotor and other changes are experienced by the patient ashead pain, tinnitus, symptoms of cerebrovascular spasm such as visualchanges, blindness, or disorientation, or some combination of these, andcontribute to the prodromal and other symptoms of an acute neurovascularheadache. Data obtained recently by Pappagallo et al. (supra) confirmthat inflammation (presumably neurogenic) of the meninges is associatedwith head pain in patients experiencing migraine.

[0174] Even in the absence of head pain, intracranial and extracranialblood vessel hyperexcitability and neuronal hyperexcitability can leadto recurrence or rebound of an acute neurovascular headache, such as amigraine, or to prolongation of the physiology of the neurovascularheadache cycle. Thus, an alternate neurovascular headache cycle mayinclude a period during which symptoms of the neurovascular headache arenot perceived by the patient, but during which period intracranial andextracranial blood vessels and nerves remain hyperexcitable, as in thecase of a series of individual headache episodes associated with acluster headache or a recurrent migraine.

[0175] Further, without wishing to be bound by any particular theory, itis believed that intranasal administration of a shorter-acting localanesthetic such as lidocaine or cocaine merely provides analgesia aloneby inhibiting transmission of nerve impulses for a relatively shortperiod—less than about an hour. Administration of a shorter-acting localanesthetic does not interrupt the physiological processes which causethe pain associated with an acute CNvD such as an acute neurovascularheadache episode. The duration of the anesthetic effect of ashorter-acting local anesthetic such as lidocaine is too short to permitintracranial and extracranial blood vessels and nerves to recover fromthe hyperexcitable state. The duration of the anesthetic effect of ashorter-acting local anesthetic is also too short to allow clearance ofvascular and perivascular humoral and cellular factors fromcerebrovascular tissue. The result of the short duration of theanesthetic effect of a shorter-acting local anesthetic is that theneurogenic inflammation continues, the neurovascular headache cyclepersists, and, once the anesthetic effect of the shorter-acting localanesthetic subsides, the neurovascular headache rebounds.

[0176] In contrast, in accordance with the present invention, anesthesiaof a DnNS such as the SPG for an effective period that permitsintracranial and extracranial nerves and intracranial and extracranialblood vessels to recover from the hyperexcitable state, arrestsneurogenic inflammation, and permits clearance of vascular andperivascular humoral and cellular factors from cerebrovascular tissue,inhibits the physiological processes which cause the occurrence orpersistence of an acute neurovascular headache. The effective period ofsuch anesthesia must be sufficient to affect these physiologicalprocesses in a beneficial manner, such as a period on the order of atleast about an hour, and preferably at least about two hours. It isunderstood that the effective period may vary among individuals.

[0177] Compromised cerebral vascular flow volume and neurogenicinflammation are believed to be related to neural and humoral factorsincluding increased local concentrations of nitric oxide, vasoactiveintestinal peptide (VIP), substance P, and other factors present inischemic or inflamed tissue. It is believed that the mechanism by whichneurogenic inflammation is arrested and recovery of nerves and bloodvessels from their hyperexcitable state is permitted followinganesthesia of a DnNS, such as the SPG, for an effective period of timeinvolves neuronal stabilization and clearance from intra- andextracranial neuronal and vascular tissues of nitric oxide, VIP,substance P, one or more neurotransmitters, one or more peptides,cellular infiltrates, or a combination of these factors. Concomitantly,blood vessel permeability is normalized and perivascular edemadecreases. Anesthesia of the DnNS for the effective period furthermorelimits release of humoral agents in cerebrovascular tissue and decreasesvasoconstriction and, by inhibition of neural mediated increases inblood vessel smooth muscle tone, may effect vasodilation, therebypermitting dissipation of local humoral and cellular factors associatedwith head pain and other symptoms. The result is that when theanesthetic effect of the local anesthetic subsides, the cranial nervesand vascular structures are no longer hyperexcitable, neurogenicinflammation has been arrested or reversed, local humoral and cellularfactors have dissipated, and thus the neurovascular headache cycle doesnot continue or rebound. This model represents a possible explanation ofthe superiority of the compositions and methods of the invention forinhibiting an acute neurovascular headache, relative to the compositionsand methods of the prior art, which were ineffective or of very limitedeffectiveness for inhibiting such disorders.

[0178] The ability to block nerve fibers which mediate the processesinvolved in the headache cycle varies with the particular localanesthetic used. Shorter-acting local anesthetics do not exhibit thesame degree of differential blockade (i.e., sensory blockade comparedwith autonomic blockade) exhibited by long-acting and persistent localanesthetics. Without wishing to be bound by any particular theory, it isbelieved that the anti-neurovascular headache efficacy exhibited bylong-acting and persistent local anesthetics, relative to thenon-efficacy of shorter-acting local anesthetics, may be attributable inwhole or in part to the degree of differential blockade capabilitiesexhibited by these types of local anesthetics.

[0179] One aspect of the present invention may be explained, at least inpart, by the hypothesis that intranasal, and preferably dorsonasal,administration of a long-acting local anesthetic pharmaceuticalcomposition inhibits an acute CNvD such as an acute neurovascularheadache episode. This treatment is hypothesized to result in anesthesiaof a DnNS such as the SPG for a period of at least about one hour, andpreferably for a period of about two hours.

[0180] Anesthesia of a DnNS such as the SPG may be achieved in any of anumber of ways. For example, at least one long-acting or persistentlocal anesthetic may be intranasally or dorsonasally administered to apatient to effect anesthesia of the DnNS. Further by way of example, asustained release formulation of a shorter-acting, long-acting, orpersistent local anesthetic may be dorsonasally administered to apatient to effect anesthesia of the DnNS. Any method known in the art ofanesthetizing nerves may be used to anesthetize the DnNS. Further by wayof example, acupuncture techniques, application of electrical potentialto a DnNS, or application of electromagnetic radiation, such as light orradio frequency radiation, to a DnNS may be used to anesthetize theDnNS. Intranasal, and preferably dorsonasal, administration of along-acting local anesthetic pharmaceutical composition is a preferredmethod of inhibiting a CNvD.

[0181] Inhibition of a migraine by dorsonasal administration of at leastone local anesthetic is an effective means of arresting the cascade ofmigraine development with consequent sterile inflammation and protractedmultisystem aggravation of symptoms, particularly where such anesthesiapersists for a period of at least about an hour, and preferably at leastabout two hours. Any of the pharmaceutical compositions described hereinmay be used for dorsonasal administration of the local anesthetic, usingthe dosages and formulations herein. As will be understood by oneskilled in the art, the optimal dosage and formulation for use with anindividual patient depends upon the age, size, condition, state ofhealth, and preferences of the patient, as well as upon the identity ofthe local anesthetic. Selection of optimal doses and formulations are,in view of the present disclosure, well within the skill of the ordinaryartisan.

[0182] Inhibition of a CNvD, a symptom of the CNvD, or both, occur veryrapidly following intranasal or dorsonasal administration of along-acting or persistent local anesthetic such as ropivacaine. Halfmaximal inhibition occurs within about three minutes, and the rate ofrebound is negligible. Photophobia and nausea are inhibited at the sametime as pain following dorsonasal administration of ropivacaine. Thecoincidental effect may be due to the wide ranging effects of intranasaladministration of the composition of the invention on multiple subpialand cerebrovascular systems. By contrast, the migraine therapeuticeffects of a serotonin receptor agonist depends on the ability ofvascular flow to effect an effective concentration of the agonist at thesite of the compromised cerebral blood vessels. The serotonin receptoragonists show intersubject variance in efficacy due to the biphasicnature of the relationship between the concentration of the agonist andthe physiological effect in vascular structures. Serotonin receptoragonists also exhibit variable efficacy due to variable effect ofindividual serotonin receptor agonists upon blood vessels within themajor cerebrovascular and subpial structures of a patient.

[0183] Combining a long-acting local anesthetic pharmaceuticalcomposition with a serotonin receptor agonist will have an additive, ifnot synergistic effect on therapeutic efficacy because the diseaseprocess is inhibited by different mechanisms. In particular, serotoninreceptor subclass 5HT1F agonists (e.g., LY334,370) are noteworthy intheir decreased side effect profile and decreased efficacy, relative toserotonin receptor subclass 5HT1D agonists, and may be used incombination with an anesthetic in a long-acting local anestheticpharmaceutical composition, such as that described herein. Such acomposition will exhibit increased efficacy, relative to the serotoninreceptor subclass 5HT1F agonist alone, regardless of the dose of theagonist.

[0184] Recurring CNvDs lead to cumulative damage and neurologicaldefects among patients afflicted with these CNvDs. For example, certainpatients who are afflicted with recurring migraines sustain permanentneurological damage. Without wishing to be bound by any particulartheory, it is postulated that anatomic and physiologic pathologies maybe secondary to the cumulative effects of repetitive pain stimuli, painimpulses, ischemia, sterile inflammation, related processes, or somecombination of these. Effective management of the neurovascular ischemiccomponent of a recurring CNvD may decrease cumulative neurologicaldamage attributable to the CNvD episodes. For example, ending theischemic component of a migraine promptly after the onset of the acutemigraine episode may decrease the damage and deficit exhibited incertain ophthalmic, basilar, or other migraine patients. Compromisednerve structures have a lower threshold of neuronal signaling to restartsubsequent CNvD episodes. Thus, decreasing the cumulative neurologicaldamage attributable to recurring CNvD episodes decreases the frequencywith which CNvD episodes are experienced by the patient.

[0185] Further without wishing to be bound by any particular theory, thepain and other neuronal signals transmitted by cerebral nerve structuresduring a CNvD episode may predispose the same or other nerve structuresto onset of a subsequent CNvD episode by processes analogous to“neuronal learning” or to central sensitization and amplification.Neuronal learning is a theory which has been described by others toexplain the apparent self-facilitating nature of pain generation andsensation. The theory of neuronal learning postulates that thetransmission of pain impulses by a particular neural pathway predisposesthat particular neural pathway to future transmission of pain impulsesin response to triggers or impulse-generating stimuli of lower magnitudethan would normally be required for pain sensation. Noxious stimuli canalso cause lasting central sensitization whereby altered sensoryprocesses in the central nervous system amplify, even in the distantfuture, subsequent pain. By way of example, it has been demonstrated insurgical patients that pre-surgical central neurologic blockade (e.g.,using epidural analgesia) reduces the sensation of postoperative pain inthe patients, even up to more than nine weeks following surgery,relative to patients who receive identical central neurologic blockadepostoperatively (Gottschalk et al., 1998, J. Amer. Med. Assoc.279:1076-1082; Woolf et al., 1993, Anesth. Analg. 77:362-379; Shis etal., 1994, Anesthesiology 80:49-56). It is believed that failure toblock transmission of pain impulses from surgically-affected sensoryneurons in the postoperatively blocked patients lowers the thresholdsensation needed to trigger pain impulse transmission from these neuronsor facilitates central amplification of pain. In contrast, it isbelieved that blockade of transmission of pain impulses from the samesurgically-affected sensory neurons in presurgically blockaded patientsprevents this threshold-lowering effect.

[0186] While still not wishing to be bound by any particular theory, itis believed that dorsonasal administration of a long-acting orpersistent local anesthetic at an early stage of a CNvD episode blocksthe transmission of pain impulses from, through, or both, relevantcerebral or other neurological structures, such that these neurologicalstructures therefore do not experience the threshold-lowering affectattributable to neuronal learning. The amount of stimulation that willinduce a subsequent episode of a CNvD is thereby not lowered.Additionally, there is no central amplification of perceived pain.Because the threshold stimulation required for inducement of CNvDepisodes is not lowered, and further because there is no centralamplification of pain, patients treated using the compositions, kits,and methods of the invention are less predisposed to subsequent CNvDepisodes, and the frequency and severity of any subsequent CNvD episodesis reduced.

[0187] Intranasal, and preferably dorsonasal, administration of along-acting local anesthetic pharmaceutical composition can also be usedto reduce the severity of an acute cerebral ischemic event, therebydecreasing neurologic deficits resulting therefrom. Without wishing tobe bound by any particular theory of operation, it is believed that thefollowing proposed mechanism explains the efficacy of this method.Tissue damage caused by an acute ischemic event is mediated by ashortage of oxygen in such tissue. This tissue damage may be alleviatedin at least two ways. Damage may be alleviated by counteracting thecause of the tissue hypoxia or by inducing supplementary oxygen deliveryto the tissue. Intranasal administration of a local anesthetic isbelieved to reduce the severity of an acute cerebral ischemic event inboth of these ways. It is believed that intranasal administration of alocal anesthetic interrupts the neural component which contributes tothe vasospasm associated with an acute cerebral ischemic event. Reliefof this neural component of the event can reduce or eliminate ischemiaassociated with the event. Furthermore, it is believed that vasodilatoryeffects of intranasally administered local anesthetics cause dilation ofblood vessels supplying the ischemic tissue, decreasing the degree ofvessel occlusion, thereby increasing blood supply to the ischemictissue. These vasodilatory effects may also increase blood flow throughthe blood vessel occlusion, for example by dilating proximal bloodvessels, thereby increasing the pressure gradient across the occlusion,resulting in less watershed ischemia.

[0188] Inhibition of Muscular Headaches

[0189] Another aspect of the present invention is based on the discoverythat intranasal, and preferably dorsonasal, administration of a localanesthetic to a human patient experiencing a muscular headache issufficient to inhibit the muscular headache or a symptom associatedtherewith. Preferably, the local anesthetic is a long-acting orpersistent local anesthetic, but shorter-acting local anesthetics arerecognized as being effective to inhibit a muscular headache as well,using this method.

[0190] Prior art methods of treating a muscular headache have focused onusing acetylsalicylic acid and its derivatives, non-steroidalanti-inflammatory drugs, sedatives, narcotics, and other drugs todecrease head pain, the primary symptom of muscular headaches.

[0191] What was not known, and what represents a surprising discovery,is that intranasal, and preferably dorsonasal, administration of a localanesthetic, preferably one which exhibits a duration of anesthesia equalto at least about a few minutes, is effective both to relieve head painduring the period of anesthesia and, more importantly, to inhibit amuscular headache.

[0192] Although all types of head pain, even head pain associated withdiverse classes of headaches, may have similar aspects of presentation,character, or pathophysiology, muscular headaches are recognized as aseparate class of headache, with distinct characteristics (HeadacheClassification Committee of the International Headache Society, 1988,Cephalalgia 8(Suppl. 7):19-28).

[0193] It has not previously been recognized that local anesthetics,when administered intranasally or dorsonasally, were capable ofrelieving muscular headache pain or muscle spasm associated withmuscular headaches.

[0194] The present invention also includes a method of inhibiting amuscular headache episode in a human patient, the method comprisingintranasally, and preferably dorsonasally, administering to the patienta composition comprising a local anesthetic and an analgesic or otherpharmaceutically active agent. Preferably, the local anesthetic is notcocaine, and administration of the composition results in relief of asymptom of the muscular headache and further results in improveddelivery of the analgesic or other agent to a cerebral neurovasculartissue of the patient. By way of example, the agent may be aspirin,acetaminophen, a non-steroidal anti-inflammatory drug, a tricyclicantidepressant, an anxiolytic, a serotonin agonist such as a triptan ora chroman compound, a narcotic, or a drug that increases cerebral levelsof gamma-aminobutyric acid. Compounds, formulations, and dosages ofanalgesics and other pharmaceutically active agents described in thismethod are known in the art. Owing, in part, to the vasodilatoryactivity of local anesthetics, these compounds may be used according tothis method at doses of about half their art-recognized doses to theirfull art-recognized doses.

[0195] The method described herein for treating a muscular headacheepisode can also be used to prevent such an episode. Certain muscularheadaches can be reliably predicted to occur following particularpatient activities prior to the onset of the episode. By treating apatient using the method described herein for treating a muscularheadache episode at a time when the episode is expected, at a time whenthe patient is under emotional distress, or at a time when the patientis exposed to another headache-triggering condition, the muscularheadache episode may be prevented.

[0196] It is believed that the compositions and methods of the inventionprovide more rapid and complete relief of muscular headache symptomsthan do known compositions and methods. Furthermore, intranasal anddorsonasal administration of local anesthetics are not associated withthe side effects known to be associated with prior art headachetreatments, and do not induce tolerance, as do prior art headachetreatments. Thus, besides being a useful headache treatment in itself,the method of the invention is a useful alternative or adjunctivetherapeutic modality with regard to prior art muscular headachetreatments.

[0197] Theory Proposed to Explain the Efficacy of the Compositions andMethods of the Invention for Inhibiting a Muscular Headache

[0198] It should be appreciated that the superiority of the compositionsand methods of the invention relative to the compositions and methods ofthe prior art does not depend upon the accuracy of the theory offered toexplain the superior results. Regardless of the mechanism by whichmuscular headaches are generated, intranasal, and preferably dorsonasal,administration of a local anesthetic, preferably a long-acting orpersistent local anesthetic, inhibits a muscular headache.

[0199] Without wishing to be bound by any particular theory, it isbelieved that the following model explains the physiological processesunderlying a muscular headache. It is believed that non-desirablesustained muscle contraction is related to local pathology, centralinfluences and multisynaptic modulation, and involves gamma efferentneuronal muscle spindle activation. Related monosynaptic conductionthrough the ventral horn augments both efferent neuronal discharge andmuscle contraction. A muscular headache cycle of pain, muscle spasm,local chemical changes, neuronal excitability or hyperexcitability,skeletal muscle blood vessel compression or spasm, and anxiety ensues.

[0200] Anesthesia of a DnNS such as the SPG effected by dorsonasaldelivery of a topical anesthetic is an effective means of inhibiting achronic muscular headache, particularly where such anesthesia persistsfor a period of at least about an hour, and preferably at least abouttwo hours. Anesthesia of the DnNS and consequent relief of associatedsymptoms occurs very rapidly following intranasal or dorsonasaladministration of a long-acting or persistent local anesthetic such asropivacaine. Half maximal arrest occurs within about three minutes. Theeffect may be due to the wide ranging effects of DnNS anesthesia onmultiple subpial and cerebrovascular systems. For example, thetrigeminal nerve is in communication with upper cervical nerves,particularly cervical nerve 2. Interruption of efferent or afferentlimbs of cervical nerve 2 would inhibit facial and scalp skeletal musclespasm, thereby breaking a major component of the muscular headachecycle.

[0201] Anesthesia of a DnNS such as the SPG for a period of at leastabout a few minutes, preferably at least about one hour, and morepreferably at least about two hours, may be achieved in any of a numberof ways. For example, a shorter-acting local anesthetic may beintranasally or dorsonasally administered to a patient to effectanesthesia of the DnNS for a period of less than about one hour, itbeing understood that such treatment may be effective only to alleviatea muscular headache episode, possibly without inhibiting the episode.Also by way of example, a long-acting or persistent local anesthetic maybe intranasally or dorsonasally administered to a patient to effectanesthesia of the DnNS. Further by way of example, a sustained releaseformulation of a shorter-acting, long-acting, or persistent localanesthetic may be dorsonasally administered to a patient to effectanesthesia of the DnNS. Any method known in the art of anesthetizingnerves may be used to anesthetize the DnNS. Further by way of example,acupuncture techniques, application of electrical potential to a DnNS,or application of electromagnetic radiation, such as light or radiofrequency radiation, to a DnNS may be used to anesthetize the DnNS.

[0202] Local Anesthetics

[0203] The chemical identity of the local anesthetic or anesthetics usedin the compositions and methods of the invention is not critical. Asdescribed herein, long-acting or persistent local anesthetics may beadministered in pharmaceutically acceptable carriers, and shorter-actinglocal anesthetics may be administered in sustained release formulationsor in conjunction with an additional compound which extends theiranesthetic effect.

[0204] Compounds having local anesthetic activity which may be used topractice the invention include, but are not limited to, articaine,ambucaine, amolanone, amylocaine, benoxinate, betoxycaine, biphenamine,bupivacaine, levo-bupivacaine, butacaine, butamben, butanilicicaine,butethamine, butoxycaine, carticaine, 2-chloroprocaine, cocaethylene,cocaine, cyclomethycaine, dibucaine, dimethisoquin, dimethocaine,diperodon, dyclonine, ecgonidine, ecgonine, ethyl aminobenzoate, ethylchloride, etidocaine, levo-etidocaine, dextro-etidocaine, beta-eucaine,euprocin, fenalcomine, fomocaine, hexylcaine, hydroxyprocaine,hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate,levoxadrol, lidocaine, lidocaine salicylate monohydrate, meperidine,mepivacaine, levo-mepivacaine, meprylcaine, metabutoxycaine, methylchloride, myrtecaine, naepaine, octacaine, orthocaine, oxethazaine,parethoxycaine, phenacaine, phenol, pipecoloxylidides, piperocaine,piridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine,proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine,quinine urea, risocaine, ropivacaine, levo-ropivacaine, salicyl alcohol,sameridine, tetracaine, tolycaine, trimecaine, veratridine, andzolamine, as well as 2-alkyl-2-alkylamino-2′, 6′-acetoxylididecompounds, such as those described in U.S. Pat. No. 3,862,321; glycerol1,2-bis-aminoalkyl ether compounds, such as those described in U.S. Pat.No. 4,117,160; benzisoxazole compounds, such as those described in U.S.Pat. No. 4,217,349; O-aminoalkylsalicylate compounds, such as thosedescribed in U.S. Pat. No. 4,298,603; heterocyclic phenoxyaminecompounds, such as those described in U.S. Pat. No. 4,379,161; 2- and3-aryl substituted imidazo(1,2-A) pyridine compounds, such as thosedescribed in U.S. Pat. No. 4,871,745, in U.S. Pat. No. 4,833,149, and inU.S. Pat. No. 4,727,145; polyorganophosphazene compounds, such as thosedescribed in U.S. Pat. No. 4,495,174 and in U.S. Pat. No. 4,636,387;tertiary-alkylamino-lower acyl-xylidide compounds, such as thosedescribed in U.S. Pat. No. 3,925,469; amidinourea compounds, such asthose described in U.S. Pat. No. 4,147,804; 3-(5′-adenylates) oflincomycin-type or clindamycin-type compounds, such as those describedin U.S. Pat. No. 4,397,845; N-substituted derivatives of1-(4′-alkylsulfonylphenyl)-2-amino-1,3-propanediol compounds, such asthose described in U.S. Pat. No. 4,632,940; tertiary aminoalkoxyphenylether compounds, such as those described in U.S. Pat. No. 4,073,917;adenosine compounds, such as adenosine and adenosine mono-, di-, andtriphosphate; lauryl polyglycol ether compounds, such as those describedin U.S. Pat. No. 5,676,955 and mixtures of such ether compounds;2-(omega-alkylaminoalkyl)-3-(4-substituted-benzylidene) phthalimidinecompounds or 2-(omega-dialkylaminoalkyl)-3-(4-substituted-benzylidene)phthalimidine compounds, such as those described in U.S. Pat. No.4,551,453; N,N,N-triethyl-N-alkyl ammonium salts, such as thosedescribed in U.S. Pat. No. 4,352,820; L-N-n-propylpipecolicacid-2,6-xylidide compounds, such as those described in U.S. Pat. No.4,695,576; N-substituted 4-piperidinecarboxamide compounds, such asthose described in U.S. Pat. No. 5,756,520; N-substituted4-phenyl-4-piperidinecarboxamide compounds, such as those described inU.S. Pat. No. 5,360,805; polymers comprising repeating units of one ormore local anesthetic moieties, such as polymers described in U.S. Pat.No. 3,914,283; compounds of formula (I):

[0205] and its derivatives, such as those described in InternationalPatent Application Publication No. WO 97/38675; compounds of formula(II):

[0206] wherein R₁₋₄, m, and P are defined as in International PatentApplication Publication No. WO 95/21821; compounds having a structuredescribed in International Patent Application Publication No. WO97/15548; compounds having a structure described in International PatentApplication Publication No. WO 97/23467; compounds having a structuredescribed in U.S. Pat. No. 4,870,086; compounds having a structuredescribed in U.S. Pat. No. 4,529,601; long-acting topical anestheticagents; long-acting topical anesthetic products of Astra {Astra Zeneca}of the “LTA” series of compounds; ester forms of any of these compounds,salts of any of these compounds, compounds otherwise chemically relatedto one of these compounds which would be effective in the presentinvention; and sustained release preparations of any of these agents, asdescribed herein. Also included are derivatives of the foregoing, wherethe derivative is any chemically related compound effective for thepresent invention.

[0207] Synonyms, including chemical names, chemical formula, and tradenames, for many of the local anesthetics described herein may be foundin Physician's Desk Reference® (Medical Economics Co., Inc., Montvale,N.J., 51st ed., 1997) or in PDR® GENERICS™ (Medical Economics Co., Inc.,Montvale, N.J., 2nd ed., 1996).

[0208] The local anesthetic is preferably selected from the groupconsisting of bupivacaine, levo-bupivacaine, ropivacaine,levo-ropivacaine, tetracaine, etidocaine, levo-etidocaine,dextro-etidocaine, and levo-mepivacaine.

[0209] Local anesthetics including, but not limited to, bupivacaine andropivacaine, which are related to aminoacyl local anesthetics exhibitintrinsic vasoactive effects on cerebral blood vessel tone and reducepain sensitivity locally. When administered dorsonasally, thesecompounds are believed to effect anesthesia of the SPG and other DnNSs,which results in increased volumetric flow of blood in cerebral bloodvessels and reduces inflammation initiated by functional ischemia. It isunderstood that the S(levo)-enantiomer of ropivacaine and theS(levo)-enantiomer of bupivacaine exhibit lower physiological toxicityand better sensory blocking properties than the correspondingR(dextro)-enantiomers. The S(levo)-enantiomer of ropivacaine ispreferred for use in the compositions and methods of the invention, asare the S(levo)-enantiomers of bupivacaine, etidocaine, and mepivacaine.

[0210] Ropivacaine exhibits lower cardiovascular and central nervoussystem toxicity than bupivacaine. Compared with bupivacaine, ropivacaineblocks nerve fibers, such as A(delta) and C sensory fibers, morepreferentially than other neurons such as motor neurons (Rosenberg etal., 1986, Br. J. Anaesth. 55:163-167). Thus, ropivacaine is preferredover bupivacaine in the compositions, kits, and methods of theinvention.

[0211] For local anesthetics which have a chiral center (e.g.,bupivacaine and ropivacaine), the local anesthetic may be a singleoptical isomer of the local anesthetic, a racemic mixture of the opticalisomers, or some other mixture of optical isomers. By way of example, a90:10, a 80:20, a 75:25, a 70:30, or a 50:50 ratio, by weight or bymolecule number, of one optical isomer to the other may be used. Thereis clinical evidence that mixtures of local anesthetics such asbupivacaine and ropivacaine, wherein about 10-25% of the anesthetic ispresent in the dextro-form can provide anesthesia of longer duration,more pronounced anesthetic effect, or both.

[0212] When the local anesthetic is an alkyl- oraryl-2-piperidinecarboxamide derivative such as mepivacaine,bupivacaine, ropivacaine, or etidocaine, the carbon atom at position 2of the piperidine ring is a chiral center, as indicated with an asteriskin formula (III), wherein R is ethyl, phenyl, or C₅-C₈ straight- orbranched-chain alkyl, and R′ is 2,6-dimethylphenyl, thiophene, or2,5-dimethylthiophene.

[0213] For these local anesthetics, it is preferred by the inventor touse the levo-enantiomer at this chiral center in the compositions, kits,apparatus, and methods of the invention.

[0214] Similarly, when the local anesthetic comprises a chiral center(indicated with an asterisk) having the structure of formula (IV), it isalso preferred that the levo-enantiomer at the chiral center be used inthe compositions, kits, and methods of the invention, wherein R and R′are as defined above and wherein either (i) each of R″ and R′″ is astraight-chain alkyl and R″ and R′″ have a total of 4 to 6 carbon atoms,or (ii) R″ and R′″ together form a heteroalkyl ring having a total of 5to 7 carbon atoms and a nitrogen atom.

[0215] By way of example, etidocaine and prilocaine each comprise achiral center within the definition of the structure of formula (IV),but having different R-groups.

[0216] It is understood by the inventor that the potency of anesthesiaeffected by local administration of an aryl-2-piperidinecarboxamidederivative such as bupivacaine, ropivacaine, or lidocaine may beincreased by increasing the lipid solubility of the derivative. This maybe achieved, for example, by increasing the lipophilic character ofsubstituent of the piperidyl nitrogen atom. The partition coefficient ofropivacaine (in an n-heptaneibuffer biphasic system) is about 2.9 timesgreater than the partition coefficient of lidocaine (Rosenberg et al.,1986, Br. J. Anaesth. 58:310-314). The partition coefficient ofbupivacaine is about 10 times greater than the partition coefficient oflidocaine (Id.). As described herein, ropivacaine and bupivacaine arelong-acting local anesthetics, while lidocaine is not a long-actinglocal anesthetic. Thus, a way in which a skilled artisan may determinewhether a particular local anesthetic is a long-acting local anestheticis to determine whether the partition coefficient of the localanesthetic in an n-heptane/aqueous biphasic system is greater than thepartition coefficient of lidocaine in such a system. If the partitioncoefficient of the particular local anesthetic is greater than thepartition coefficient of lidocaine, then the particular local anestheticis likely a long-acting local anesthetic. Preferably, the partitioncoefficient of the particular local anesthetic is at least 2.9 timesgreater than the partition coefficient of lidocaine. The potency ofanesthesia of a local anesthetic may be increased by modifying thechemical structure of the local anesthetic in such a manner as toincrease the partition coefficient of the local anesthetic, for exampleby adding hydrophobic substituents to the local anesthetic molecule orlengthening hydrophobic substituents of the local anesthetic.Preferably, the local anesthetic used in the compositions, kits, andmethods of the present invention has a partition coefficient in ann-heptane/aqueous biphasic system greater than the partition coefficientof lidocaine in such a system.

[0217] It is understood by the inventor that the duration of anesthesiaeffected by local administration of an anesthetic such as anaryl-2-piperadinecarboxamide derivative is related to the proportion ofthe anesthetic which is bound to protein in vivo. Approximately 95% ofeach of bupivacaine and ropivacaine is bound to protein in vivo, whileonly about 65% of lidocaine is bound to protein in vivo. Thus, anotherway in which a skilled artisan may determine whether a particular localanesthetic is a long-acting local anesthetic is to determine whether theproportion of the particular local anesthetic which is bound to proteinin vivo is greater than the proportion of lidocaine which is bound toprotein in vivo. If the proportion of the particular local anestheticwhich is bound to protein in vivo is greater than the proportion oflidocaine which is bound to protein in vivo, then the particular localanesthetic is likely a long-acting local anesthetic. The proportion ofthe local anesthetic used in the compositions, kits, and methods of thepresent invention which is bound to protein in vivo should be greaterthan about 65%. Preferably, the proportion of the particular localanesthetic which is bound to protein in vivo is at least about 95%.

[0218] The duration of anesthesia of a local anesthetic may be increasedby modifying the chemical structure of the local anesthetic in such amanner as to increase the proportion of the particular local anestheticwhich is bound to protein in vivo, for example by adding chemicalsubstituents to the particular local anesthetic molecule which arecapable of binding, covalently or non-covalently, to protein moieties.

[0219] The therapeutic effects of local anesthetics in the presentinvention are not directly proportional to their prior art use elsewherein the body as local anesthetics. Thus, the duration and pain-relievingeffects of the long-acting and persistent local anesthetics in thepresent invention are enhanced, compared to their use as localanesthetics elsewhere in the body. The enhanced duration andpain-relieving effects of the long-acting and persistent localanesthetics of the present invention are surprising, compared with theeffects achieved using other methods of using local anesthetics.

[0220] For example, administration of ropivacaine may anesthetize anerve structure for a period about 1.5 to about 4 times that achieved byadministration of lidocaine, depending on the location and type of thenerve structure, and further depending on the concentration and totaldose of the local anesthetic and on the presence of vasoconstrictors orother drugs which affect either uptake of the local anesthetic by thenerve structure or clearance of the local anesthetic from the anatomicalsite of the nerve structure. The difference between the period ofanesthesia effected by administration of ropivacaine and the period ofanesthesia effected by administration of lidocaine is less pronouncedwhen the site of administration is a skin or mucosal surface. Thus, onewould expect that if lidocaine and ropivacaine affected CNvDs and theirsymptoms by the same mechanism, administration of ropivacaine to apatient afflicted with a CNvD would provide relief lasting no more thanabout 4 times as long as the relief provided by administration oflidocaine, and probably closer to no more than about 1.5 times as long.In fact, as described herein, the relief provided by administration ofropivacaine to CNvD patients, such as migraine patients, persisted farlonger than the duration of relief provided by administration oflidocaine to such patients. This surprising result further highlightsthe difference between prior art methods of relieving a symptom of aCNvD and the methods of the invention for inhibiting a CNvD.

[0221] The use of microdroplets comprising a general anesthetic toeffect local anesthesia are known and have been described, for examplein U.S. Pat. No. 4,622,219. Liposomal preparations of local anestheticsare also known and have been described, for example in U.S. Pat. No.4,937,078. However, neither the use of a general anesthetic inmicrodroplet form nor the use of a sustained release preparation of oneor more local anesthetics has been described prior to the presentdisclosure for the purpose of inhibiting, or otherwise treating an acuteCNvD or for the purpose of reducing the severity of an acute cerebralischemic event in a human patient. The preparations and uses of generalanesthetics in microdroplet form and the preparations and uses ofliposomal preparations of one or more local anesthetics are includedwithin the compositions, kits, apparatus, and methods of the invention.General anesthetics which can be used in microdroplet form include, butare not limited to, desflurane, diazepam, enflurane, etomidate,halothane, isoflurane, methohexital sodium, methoxyflurane, midazolamhydrochloride, propofol, sevoflurane, and thiopental sodium.

[0222] Dosing Information

[0223] The following dosing information is believed to be useful for theCNvD-inhibiting methods and the muscular headache-inhibiting methods ofthe invention. Dosing information relevant to the systemic drug deliverymethod of the invention is described separately in the portion of thepresent disclosure which describes that method.

[0224] Various dosage forms may be made which comprise a localanesthetic at a concentration of about 0.01% to about 53% by weight,preferably a concentration of about 0.25% to about 10% by weight, morepreferably about 0.5% to about 5% by weight, and even more preferably atabout 2.5% by weight. The pharmaceutical composition should beformulated to deliver about 10 micrograms to about 2.5 grams of thelocal anesthetic to each nostril of a patient, and preferably to deliverabout 10 micrograms to about 1 gram. Unit dosage forms containing anamount of the pharmaceutical composition in these ranges may be used.When the pharmaceutical composition is in the form of a liquid fortopical application (e.g., a spray), a dose of the pharmaceuticalcomposition may be contained, for example in a volume of about 0.5milliliters to about 5 milliliters, and preferably in a volume of about1 milliliter to about 3 milliliters, for delivery to each nostril. Suchliquid pharmaceutical compositions preferably contain the localanesthetic at a concentration of about 0.01% to about 20% (w/v), morepreferably about 0.25% to about 5% (w/v). When the pharmaceuticalcomposition is in the form of a solid, semi-solid, gel, foam, mousse,creme, emulsion, or the like, the pharmaceutical composition may beformulated to contain about 10 micrograms to about 2.5 grams of thelocal anesthetic to the patient per nostril in a volume of about 0.5milliliters to about the capacity of the nasal cavity. In oneembodiment, the local anesthetic is dorsonasally administered in a totalamount from about 1 milligram to about 70 milligrams (although thisamount may alternatively be administered to each nostril), andpreferably in an amount from about 10 micrograms to about 50 milligrams.The concentration of the local anesthetic in the solid, semi-solid, gel,foam, mousse, creme, or emulsion form is preferably about 0.1% to about53% (w/w), more preferably about 0.2% to about 20% (w/w).

[0225] A bulk form of a long-acting local anesthetic pharmaceuticalcomposition may be made and administered to a patient in one or moredoses which comprise the dosage amounts described in the precedingparagraph.

[0226] Pharmaceutical Compositions

[0227] The long-acting local anesthetic pharmaceutical composition thatis useful in the methods of the invention may be intranasally ordorsonasally administered in a variety of formulations that can be madereadily by one of skill in the art of pharmacology in view of thepresent disclosure. Formulations which are useful for intranasaladministration of the pharmaceutical composition of the inventioninclude, but are not limited to, jelly, creme, gel, foam, mousse,semi-solid, emulsion, sol-gel, foam, a eutectic mixture, liquid,droplet, aerosol, powder, microsomes, liposome, sustained release,degradable polymer, polymer microspheres, impregnated film, fiber, orpatch, coated film, fiber, or patch, and other similar dosage forms. Thepharmaceutical composition of the invention may contain one or more thanone local anesthetic agent. When the pharmaceutical composition containsmore than one local anesthetic agent, the agents may be mixed insubstantially any ratio such as, for example, a eutectic ratio asdescribed in U.S. Pat. No. 4,562,060. Eutectic mixtures of localanesthetics can be rapidly and more easily taken up by submucosalstructures such as nerves, and thus are useful for submucosal nerveblock. In addition, levo local anesthetics are vasoconstrictors.Eutectic mixtures of a local anesthetic with a vasoconstricting agent(e.g., a levo local anesthetic) can exhibit prolonged local anestheticactivity and reduced systemic uptake relative to non-eutectic mixturesof the same local anesthetic.

[0228] In addition to the local anesthetic, such pharmaceuticalcompositions may contain pharmaceutically acceptable carriers and otheringredients known to enhance and facilitate drug administration with theadditional pharmaceutical agents disclosed herein. Compounds,formulations, and dosages of the additional pharmaceutically activeagents described in this method are known in the art. Owing, in part, tothe vasodilatory activity of local anesthetics, these compounds may beused according to this method at doses of about half theirart-recognized doses to their full art-recognized doses.

[0229] Such pharmaceutical compositions may also contain ingredients toenhance sensory acceptability of the composition to a human patient,such as aromatic, aromatherapeutic, or pleasant-tasting substances. Thepharmaceutical compositions may also, for example, be made in the formof a flexible solid or semisolid carrier comprising the localanesthetic, such as one of the carriers described in U.S. Pat. No.5,332,576 or in U.S. Pat. No. 5,234,957; or in the form of suspendedmicrospheres, such as those described in U.S. Pat. No. 5,227,165. Solidand semi-solid formulations of a shorter-acting, a long-acting, or apersistent local anesthetic are preferred in the compositions, methods,and kits of the inventions, because such preparations improve localanesthetic localization. In these forms, there is less dilution of thelocal anesthetic by body fluids and less transport of the localanesthetic to an unintended body location. Furthermore, it is believedthat these formulations will reduce or minimize unintended side effectssuch as disagreeable taste, oropharyngeal numbness, dysphasia, andcompromise of protective reflexes. In these formulations, a lower amountof local anesthetic may be used, relative to other formulations.

[0230] Numerous pharmaceutically acceptable carriers are known in theart, as are methods of combining such carriers with local anesthetics.Examples of such carriers and methods are described, for example, inGenaro, ed., 1985, Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa.

[0231] It is understood that the pharmaceutical composition of theinvention may comprise a combination of any of the forms describedherein. By way of example, microparticles, microsomes, or liposomescomprising a local anesthetic may be suspended in a solution or otherformulation of the same or a different local anesthetic, whereby thesolution or other formulation provides a rapid onset of anesthesia andthe local anesthetic in the form of microparticles, microsomes, orliposomes provides a sustained duration of anesthesia. Sustained releasepreparations may comprise a slowly-released formulation of a localanesthetic. Inclusion of another local anesthetic in such formulations,in a free or salt (i.e., not slowly-released) form confers to theformulation the ability to act both with a rapid onset of anesthesia anda sustained duration of anesthesia. All such combinations offormulations described herein are included in the invention.

[0232] The long-acting local anesthetic pharmaceutical compositionuseful for practicing the invention must be administered in a dosesufficient to inhibit the CNvD for at least about one hour, andpreferably for at least about two hours. Doses of the long-acting localanesthetic pharmaceutical composition may be administered in a singledose, in multiple doses, in sustained release doses, or continuously.

[0233] The local anesthetic(s) may be present in the pharmaceuticalcomposition at any concentration from a very dilute concentrationthrough the solubility limit of the local anesthetic in the medium inwhich it is delivered. The local anesthetic(s) may also be present at aconcentration greater than the solubility limit of the local anestheticin the medium in which it is delivered by using a crystalline,microcrystalline, or amorphous solid form of the local anesthetic,preferably suspended in a gel, foam, mousse, creme, liquid, liposome,microsome, solid polymeric matrix, or the like. In various embodiments,the local anesthetic may be administered in the form of a eutecticmixture of local anesthetics, such as described in U.S. Pat. No.4,562,060, in the form of encapsulated or embedded local anesthetic,such as described in U.S. Pat. No. 5,085,868, in the form of anoil-in-water emulsion, such as described in U.S. Pat. No. 5,660,837, orin the form of an emulsion, a creme, a eutectic mixture, or amicroemulsion, such as described in International Patent ApplicationPublication No. WO 97/38675, particularly one having thermoreversiblegelling properties. Because the nasal cavity is normally cooler than gumpockets, the environment disclosed in International Patent ApplicationPublication No. WO 97/38675, a composition having thermoreversiblegelling properties, wherein the composition is a fluid at about 20° C.and a gel or semi-solid at the temperature in the human nasal cavity(i.e., about 30-37° C.), is preferred. Any of these compositions may beconveniently delivered dorsonasally and, once so delivered, will beavailable where placed within the nasal cavity for a sustained periodafter administration and will spread or drip into other tissues to alesser degree than would a liquid composition. By using one of theseformulations, less of the active compound yields greater therapeuticresults and has significantly decreased side effects, such as local andsystemic toxicity, tongue and oropharyngeal numbness, discomfort, badtaste, dysphasia, and possible compromise of protective airway reflexes.

[0234] Other possible formulations may be made by of one of skill in theart of pharmacology in view of this disclosure without departing fromthe spirit of the invention. See, for example, (Genaro, ed., 1985,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.)for a number of forms of typical pharmaceutical compositions that may beadapted readily to the present invention in view of this disclosure.

[0235] Co-Administration of a Local Anesthetic with Another Migraine orMuscular Headache Therapeutic Agent

[0236] Numerous pharmaceutically active agents are thought to exhibittheir limited therapeutic activity by virtue of the ability of the agentto interact with one or more receptors present on the surface ofcerebral blood vessels or other structures. By way of example, migrainetherapeutic agents known as serotonin receptor agonists include suchagents as sumatriptan and zolmitriptan, and are believed to interactwith serotonin receptors. In order to exhibit their pharmacologicaleffects, such agents must gain access by systemic vascular delivery tocerebral blood vessels which have altered vascular flow during an acutemigraine episode (Scott, 1994, Clin. Pharmacokinet. 27:337-344) and mustachieve a critical concentration at the cerebrovascular location of thecorresponding receptor(s) in the compromised area. Thus, thesepharmaceutically active agents must be administered at the onset of anacute migraine episode in order to avoid the cascade of inflammationthat follows initiation of the episode (Limmroth et al., 1996, Curr.Opin. Neurol. 9:206-210). Following delivery of one of these agents tothe compromised area of a cerebral blood vessel, the concentration ofthe drug gradually decreases at those sites, and rebound can occur.

[0237] Topical local anesthetics are vasodilators and therefore inhibitvasoconstriction, with the exceptions of cocaine, which is avasoconstrictor. It is believed that the vasodilatory effects of topicallocal anesthetic administration results from both a direct effect of theanesthetic upon the affected blood vessel and from an indirect effect ofthe anesthetic upon nerve structures associated with the blood vessel.

[0238] In normal states, most blood vessels, particularly those ofsmaller diameter, do not transport blood because they are not open, dueto constriction of blood vessels located proximal thereto with respectto the heart or due to increased muscle tone in the blood vessel wallitself. Should these vessels open at once, profound hypotension woulddevelop immediately, resulting in shock. Many and complex mechanisms areinvolved in the regulation of blood vessel tone and blood circulation.Hence, in any given tissue or organ, many blood vessels are closed.Blood vessel recruitment refers to a process whereby closed or partiallyconstricted blood vessels are opened or dilated. This increases thenumber and surface area of blood vessels available for uptake and allowsgreater blood flow through these vessels. The latter mechanism increasesdrug transport away, and this decreases local blood drug concentration,favoring drug diffusion into the blood. All of these mechanisms increasedrug uptake and transport. Surface vasodilation effected by anintranasally or dorsonasally administered local anesthetic other thancocaine promotes greater blood vessel recruitment and therefore, greatersystemic uptake of the pharmaceutically active agent administered inconjunction with the local anesthetic. Hence, co-administration of alocal anesthetic and a pharmaceutically active agent results in a morerapid and greater systemic uptake of the pharmaceutically active agent.This produces a more rapid and greater concentration of thepharmaceutically active agent at the affected site.

[0239] Furthermore, vasodilation of arterial structures which passthrough the intranasal mucosa to feed other relevant neural structureswill result in increased delivery of intranasally administeredpharmaceutically active agents directly to target sites, especially ifarterial blood flows through an area to which the agent and anestheticare administered. For example, the sphenopalatine artery provides bloodsupply to much of the middle turbinate of the human nose, to the regionof the nasal epithelium overlying the SPG, and to the SPG. Withoutwishing to be bound by any particular theory, it is believed that theanesthetizing effect of local anesthetics such as bupivacaine inducesvasodilation of arterial structures coursing through local tissue on theway to the brain and other relevant neural structures, and increasesagent delivery. Additionally, the decreased extracranial andintracranial vasospasm and vasodilation which result from anesthesia ofthe SPG increases blood flow to relevant structures and thereforeincreases drug delivery to relevant tissues even further. Hence,intranasal administration of local anesthetic(s) induces both local andintracranial vasodilation and decreases or prevents vasoconstrictioncaused by normal autoregulatory processes, by neurally mediatedprocesses, or by release of neurotransmitters, neuropeptides, or otherfactors which are associated with an acute CNvD or muscular headache.Thus, administration of a local anesthetic to the region of the nasalepithelium overlying the SPG and to other regions of the epitheliumlocated nearby facilitates transport of a pharmaceutically active agentfrom the surface of the nasal epithelium directly into relevant venous,capillary, and arterial vessels and into the general systemiccirculation where intracranial vasodilation or decreased vasospasmresults in increased active agent delivery to sites at which it exhibitsits pharmaceutical activity.

[0240] Therefore, it is anticipated that dorsonasal delivery of acomposition which comprises a long-acting or persistent local anestheticand a pharmaceutically active agent will result in greater localdelivery of the agent to a cerebral neurovascular tissue than could beachieved by dorsonasal delivery of the agent alone.

[0241] Furthermore, if agents, such as sumatriptan and ropivacaine, forexample, are believed to have different mechanisms of action, it isbelieved that the therapeutic effects of the two compounds will bepharmacodynamically synergistic, or at least additive. This is yetanother manner that co-administration of a local anesthetic and anotherpharmaceutical agent is advantageous.

[0242] Without wishing to be bound by any particular theory ofoperation, it is believed that the co-administered compositions inhibitthe headache and diminish the likelihood that the headache will reboundor recur. This is believed to be especially true for patients who areafflicted with a plurality of distinct headaches or patients whoexperience separate headache triggers in series.

[0243] The present invention includes a method of inhibiting aneurovascular or muscular headache in a human patient, the methodcomprising intranasally, and preferably dorsonasally, administering tothe patient a composition comprising at least one local anesthetic and apharmaceutically active agent effective for treatment of the headache.Preferably, the local anesthetic is a long-acting local anesthetic, apersistent local anesthetic, or a sustained release formulation of alocal anesthetic other than cocaine, whereby intranasal, and preferablydorsonasal, administration of the composition results in improved uptakeof the pharmaceutically active agent by a cerebral neurovascular tissueof the patient and to enhancement of the pharmaceutical activity of theagent.

[0244] By way of example, when the headache is a migraine, compositionsfor inhibiting the migraine and co-administering a migraine therapeuticagent include a sustained release formulation of a compositioncomprising sumatriptan (e.g., IMITREX™, Glaxo-Wellcome Inc., ResearchTriangle, N.C.) and lidocaine, a composition comprising zolmitriptan(e.g., ZOMIG™, Zeneca Pharmaceuticals, Wilmington, Del.) andbupivacaine, a composition comprising rizatriptan (e.g., MAXALT™, Merck& Co., West Point, Pa.) and ropivacaine, a composition comprisingnaratriptan (e.g., NARAMIG™, Glaxo-Wellcome Inc., Research Triangle,N.C.) and tetracaine, and a composition comprising a beta blocker andetidocaine.

[0245] Further by way of example, when the headache is a muscularheadache, compositions for inhibiting the muscular headache andco-administering a muscular headache therapeutic agent includecompositions comprising a local anesthetic ingredient selected from thegroup consisting of a persistent local anesthetic, a long-acting localanesthetic, and a sustained release formulation of a local anestheticand an additional pharmaceutically active agent selected from the groupconsisting of a vasoconstrictor, epinephrine, norepinephrine,phenylephrine, methysergide, propanolol, a calcium channel blocker,verapamil, ergot, an ergotamine preparation, dihydroergotamine, aserotonin agonist, sumatriptan, zolmitriptan, rizatriptan, naratriptan,a chroman compound, aspirin, acetaminophen, a non-steroidalanti-inflammatory drug, caffeine, a narcotic, butorphanol tartrate,meperidine, a mast cell degranulation inhibitor, cromolyn sodium,eucalyptol, tetrodotoxin, desoxytetrodotoxin, saxitoxin, an organicacid, a sulfite salt, an acid salt, a glucocorticoid compound, a steroidester, magnesium or lithium ions, a centrally-acting analgesic, a betablocker, an agent that increases cerebral levels of gamma-aminobutyricacid, butalbital, a benzodiazepine, valproat, gabapentin, divalproexsodium, a tri-cyclic antidepressant, a narcotic analgesic, an oralmuscle relaxant, a tranquilizer, a muscle relaxant, and anothercompound.

[0246] The local anesthetic compounds, formulations, dosages, andmethods of administration which are useful for this method of theinvention are substantially the same as those described herein withrespect to inhibiting a neurovascular headache, a muscular headache, ora CNvD. Compounds, formulations, and dosages of the otherpharmaceutically active agents described in this method are known in theart. Owing, in part, to the vasodilatory activity of local anesthetics,these compounds may be used according to this method at doses of abouthalf their art-recognized doses to their full art-recognized doses.

[0247] The composition may comprise a local anesthetic and apharmaceutically active agent which is effective for treating a CNvD ora muscular headache. By way of example, such a composition may compriseropivacaine and an additional ingredient. The additional ingredient may,for example, be a serotonin receptor agonist, including, but not limitedto, a triptan, e.g., sumatriptan or a chroman compound such as one ofthe compounds described in U.S. Pat. Nos. 5,387,587; 5,420,151;5,639,772; and 5,656,657, a non-steroidal anti-inflammatory drug, ananti-emetic, or a mast cell degranulation inhibitor such as cromolynsodium.

[0248] In addition, the composition may comprise an agent whichincreases or prolongs either or both of the anesthetic effect and thetissue uptake of the local anesthetic. Such agents include, for example,an n-glycofurol compound, such as one of the compounds described in U.S.Pat. No. 5,428,006, eucalyptol, a toxin such as tetrodotoxin,desoxytetrodotoxin, or saxitoxin, an organic acid, a sulfite salt, anacid salt, magnesium or lithium ions, and a centrally-acting analgesic.

[0249] In addition, the composition may be a combination of a betablocker and a local anesthetic, as described, for example, in EuropeanPatent No. 754060. The agent may also be a drug that increases cerebrallevels of gamma-aminobutyric acid (GABA), either by increasing GABAsynthesis or decreasing GABA breakdown. Such GABA-affecting agentsinclude, for example, butalbital, benzodiazepines, valproat, gabapentin,and divalproex sodium. The agent may also be an agent effective fortreatment or prevention of neurodegenerative disorders such as, forexample, (S)-alpha-phenyl-2-pyridineethanamine (S)-malate, as describedin European Patent No. 970813. Furthermore, the agent may be a compoundwhich decreases inflammation, including, for example, a glucocorticoidcompound such as a steroid ester. Compounds, formulations, and dosagesof vasoconstrictors and other pharmaceutically active agents describedin this method are known in the art. Owing, in part, to the vasodilatoryactivity of local anesthetics, each of these compounds may be usedaccording to this method at doses of about half their art-recognizeddoses to their full art-recognized doses.

[0250] In a patient refractory to monotherapy or treatment using a localanesthetic composition comprising only one additional compound, thecomposition may be combined with one, two, or more additional compounds,and this combined composition may prove to have therapeutic effectswhich are synergistic, or at least additive, with respect to each of theindividual ingredients. By way of example, such a combined compositionmay comprise a long-acting or persistent local anesthetic, abeta-blocker, and a serotonin receptor agonist. Other examples include acombined composition comprising a long-acting or persistent localanesthetic and an anti-epileptic compounds such as phenytoin sodium(e.g., Dilantin®, Parke-Davis, Morris Plains, N.J.), a combinedcomposition comprising a long-acting or persistent local anesthetic anda serotonin receptor agonist, a serotonin subclass 5HT1F receptoragonist, LY334,370, and a combined composition comprising a long-actingor persistent local anesthetic and a sesquiterpene lactone (e.g., acompound such as parthanolide, obtained from an herb such as feverfew{Tanacetum parthenium}).

[0251] Methods of Effecting Intranasal or Dorsonasal Administration

[0252] Intranasal administration of a composition may be effected by anymethod by which the composition is provided to any portion of the nasalepithelium. Intranasal administration of a composition comprising alocal anesthetic according to certain methods of the invention ispreferably effected by dorsonasal administration of the localanesthetic.

[0253] Dorsonasal administration of a pharmaceutical composition may beeffected by any method or route which results in delivery of thecomposition to a tissue, fluid, or surface of a human, whereby acomponent of the composition is provided to a DnNS either directly or bydiffusion through tissue or fluid interposed between the DnNS and thesite of administration. For example, dorsonasal administration of acomposition comprising a local anesthetic may be effected by injecting acomposition directly into a DnNS or by topically applying thecomposition to a tissue located in close anatomic proximity to the SPG,whereby the local anesthetic is capable of diffusing from the tissue toa DnNS such as the SPG. Topical dorsonasal administration may beaccomplished by an intranasal route or by an oropharyngeal route, forexample. As described herein, nasal drip methods, nasal sprayapplication methods, and mechanical application methods may be used toeffect topical dorsonasal administration of a composition comprising alocal anesthetic.

[0254] Intranasal administration of the composition of the invention maybe improved if the nasal cavity is rinsed, treated with a decongestant,or otherwise cleared of material which might impede intranasal deliveryprior to administration of the composition.

[0255] As described herein in Example 1, dorsonasal administration ofropivacaine to patients afflicted with migraine using an intranasalspray method, an intranasal drip method, or an intranasal cotton swabmethod yielded different response rates and different values for theefficacy of ropivacaine for relief of migraine. Although drip and spraymethods resulted in wider ropivacaine distribution within the nasalcavity, direct application of ropivacaine to the region of the nasalepithelium overlying the SPG using a cotton swab yielded the most rapidand most effective inhibition of migraine.

[0256] The pharmaceutical composition that is useful in the methods ofthe invention may be administered topically in the types of formulationsnoted herein. Intranasal, and preferably dorsonasal, administration ofthe composition may be achieved by providing a mist or aerosol spraycomprising the composition to the nasal cavity via the nostril, byproviding drops or a stream of liquid comprising the-composition to thenasal cavity via the nostril or by injection of the liquid using ahypodermic needle which penetrates the facial skin of the patient, bydirectly applying the composition dorsonasally using a flexible oranatomically-shaped applicator inserted through the nose or mouth of thepatient, including an applicator or implant which is left in place overa period of time, by introducing into the nasal cavity a liquid, gel,semi-solid, powder, or foam comprising the composition, or by any othermeans known to one of skill in the art of pharmaceutical delivery inview of this disclosure.

[0257] Intranasal, and preferably dorsonasal, administration of apharmaceutical composition to a human has distinct advantages relativeto other routes of administration. By administering a compositionintranasally or dorsonasally, a high local concentration of thecomposition in a relevant neural structure, and possibly in the cerebralneurovasculature, may be achieved relative to the systemic concentrationof the composition. Local delivery is advantageous in situations inwhich systemic exposure to the composition is undesirable, eitherbecause the composition is metabolized systemically or because systemicexposure results in harmful symptoms. By way of example, systemicadministration of a local anesthetic such as bupivacaine is undesirablebecause bupivacaine is metabolized in the liver and because systemicadministration of a relatively large amount of bupivacaine is known tocause serious adverse effects.

[0258] Another advantage of intranasal or dorsonasal administration of acompound, at least where local cerebral neurovascular delivery isdesired, is that a lesser amount of drug may be administered than wouldbe necessary to administer via a different route. Absorption ofintranasally or dorsonasally delivered drug into cerebral neurovasculartissue enables the patient to avoid digestive or at least some hepaticdrug metabolism which could occur, for instance, if the drug wereadministered orally. Furthermore, intranasal or dorsonasal delivery of adrug requires less intensive intervention by a medical professional thansome other delivery methods, such as intravenous delivery.Self-medication by an intranasal or dorsonasal route is practical, asevidenced by the many nasal and pulmonary delivery devices and drugformulations which are commercially available.

[0259] DnNSs may not be directly accessible via the nasal cavity.However, because of the anatomic proximity of DnNSs to the nasalepithelium, anesthesia of a DnNS can be effected by topicaladministration of a local anesthetic to the region of the nasalepithelium overlying the SPG or to the region of the nasal epitheliumnear that region. For example, within the nasal cavity, the SPG liesdorsal to the posterior tip of the middle concha, and is covered by thenasal epithelium at a variable depth of one to nine millimeters (Sluder,1908, N.Y. State J. Med. 27:8-13; Sluder, 1909, N.Y. State J. Med.28:293-298). Thus, a compound applied to the surface of the nasalepithelium at or near the region of the nasal epithelium overlying theSPG, such as the surface of the nasal epithelium dorsal to the posteriortip of the middle concha can diffuse through the epithelium and anyintervening tissue or fluid to reach the SPG.

[0260] The SPG, which is sometimes designated the pterygopalatineganglion, is located in the pterygopalatine fossa of the human skull,close to the sphenopalatine foramen and close to the pterygoid canal.The SPG is situated below the maxillary nerve where the maxillary nervecrosses the pterygopalatine fossa. Although it is also connectedfunctionally with the facial nerve, the SPG is intimately related withthe maxillary division of the trigeminal nerve and its branches. Theparasympathetic root of the SPG is formed by the nerve of the pterygoidcanal, which enters the SPG posteriorly. The fibers of theparasympathetic root of the SPG are believed to arise from a speciallacrimatory nucleus in the lower part of the pons and run in the sensoryroot of the facial nerve and its greater petrosal branch before thelatter unites with the deep petrosal branch to form the nerve of thepterygoid canal. The sympathetic root of the SPG is also incorporated inthe nerve of the pterygoid canal. The fibers of the sympathetic root ofthe SPG are postganglionic, arise in the superior cervical ganglion, andtravel in the internal carotid plexus and the deep petrosal nerve. Thevidian nerve is located in close proximity to the SPG, and the efficacyof local anesthetics for inhibiting an acute CNvD may arise, in whole orin part, from anesthesia of the vidian nerve or another DnNS located inclose anatomic proximity to the SPG. It is also known that thetrigeminal nerve has anatomical and functional relationship(s) tocervical nerve 2. Other DnNSs which are located in close anatomicproximity to the SPG include, but are not limited to, the cavernoussinus ganglion, the carotid sinus ganglion, numerous branches of themaxillary nerve, the ethmoidal nerve, and the ethmoidal ganglion.

[0261] The ability of a compound to diffuse from the surface of thenasal epithelium to a DnNS such as the SPG depends, of course, on theability of the compound to diffuse through bodily tissues and fluids.Thus, compounds to be delivered to a DnNS by topical application to thenasal epithelium are preferably diffusible through both aqueoussolutions and lipids.

[0262] Local anesthetics which are related to the class of localanesthetics designated aminoacyl local anesthetics exhibit both suitableaqueous solubility and suitable lipid solubility for use in the methodsof the invention. It is believed that such local anesthetics are able todiffuse into nerves in their neutral, uncharged state, and that suchlocal anesthetics assume their pharmacologically active, charged statewithin nerve cells.

[0263] In the case of delivery of a local anesthetic to a DnNS such asthe SPG via topical application of the anesthetic to the nasalepithelium, it is preferable that the anesthetic be sufficientlydiffusible through bodily tissues and fluids and have a sufficientlylong half-life in vivo that the anesthetic is able to diffuse from theepithelium to the DnNS in an amount and for a duration sufficient toanesthetize the DnNS or otherwise inhibit the physiological processesthat result in one or more symptoms of the CNvD, such as a period on theorder of at least about one hour, and preferably at least about twohours. On the other hand, the diffusivity through bodily tissues andfluids and the in vivo half-life of the anesthetic must not be so highand long, respectively, that the anesthetic is delivered systemically inan amount sufficient to cause the adverse effects known to be associatedwith systemic administration of local anesthetics (see, e.g.,Physician's Desk Reference®, Medical Economics Co., Inc., Montvale,N.J., 51 st ed., 1997, pp. 424-427).

[0264] Apparatus for Intranasal or Dorsonasal Administration of aComposition

[0265] Particularly contemplated apparatus for intranasal or dorsonasaldelivery of a composition to a human patient according to the methods ofthe invention include, but are not limited to, an anatomically-shapedapplicator, a metered dose dispenser, a non-metered dose dispenser, asqueezable dispenser, a pump dispenser, a spray dispenser, a foamdispenser, a powder dispenser, an aerosol dispenser, a dispensercontaining a propellant, an inhalation dispenser, a patch comprising thecomposition, an implant comprising the composition, a soft pipette withan elastomeric bulb in fluid communication with a reservoir containingthe composition, a dropper for directing the composition past theconchae of the patient to an intranasal nerve structure (InNS, includinga DnNS, but not limited to DnNSs), or intranasal blood vessel (InBV), aswab having an absorbent portion impregnated with the composition, aswab having an anatomically-shaped portion comprising an absorbentportion impregnated with the composition, and a swab having a compressedabsorbent portion in fluid communication with a reservoir containing thecomposition. An anatomically-shaped applicator is one which has a shapewhich permits insertion of the applicator into the nose or mouth of ahuman and which enables contact of the composition delivered by theapplicator with the surface of the region of the nasal epitheliumoverlying the InNS or with a surface of the nasal epithelium near theregion of the nasal epithelium overlying the InNS (e.g., a DnNS such asthe SPG). It is preferred that the shape and/or materials of theapparatus be selected for comfortable insertion or application via anintranasal route. The apparatus preferably is adapted to contact eithera superior portion of the nasal epithelium or a portion of the nasalepithelium that overlies a DnNS.

[0266] Another embodiment of an apparatus for intranasal or dorsonasaldelivery of a pharmaceutical composition of the invention comprises abody having a plurality of passages through which a composition may bedelivered. The device may be designed so that the pharmaceuticalcomposition of the invention is delivered through each passage, thepassages being individually or collectively connected to, for example, aplurality of orifices in an anatomically-shaped applicator whereby theorifices direct delivery of the composition to a plurality of locationswithin the nasal cavity when the applicator is inserted into the nose ofa patient and operated. The device may alternately be designed so thatthe pharmaceutical composition of the invention is delivered through oneor more passages and an additional pharmaceutically active agent isdelivered through the same passages or through one or more differentpassages. Alternately, the device may comprise components of thepharmaceutical composition of the invention which are separatelydelivered through one or more passages of the device and mixed either ina passage of the device or in the nasal cavity of the patient.

[0267] Devices which contain, deliver, or produce a semi-solidlong-acting local anesthetic composition are contemplated. To use one ofthese devices, an outlet of the device is situated in fluidcommunication with one of or both of the nostrils of a patient. A solid,foam, semi-solid, foam-forming fluid, or another fluid which exhibits anincrease in viscosity upon administration, such as one of the type knownin the art, is provided to the outlet, whereby it passes into thenostril of the patient, filling or partially filling the nasal cavity. Alocal anesthetic in the composition contacts the walls of the nasalcavity, preferably in a dorsonasal location, and the local anesthetic isthereby administered to the patient. The devices described herein can beused to deliver substantially any composition or material to theportion(s) of the nasal epithelium for which they are adapted.

[0268] Directed Intranasal Drug Delivery Devices

[0269] There are several known devices for effecting intranasal deliveryof a drug or other non-gaseous pharmaceutically acceptable preparation.Such devices include, for example, liquid-containing squeeze bottles,liquid-containing pressurized containers, liquid-containing pump-typecontainers, droppers, microfine powder dispersers, and nebulizers.Although each of these prior art devices may be used to intranasallyadminister a pharmaceutical composition (e.g., according to any of themethods described herein), each of these devices has certain drawbacksand shortcomings which make their use for directed intranasaladministration of compositions (e.g., for dorsonasal administration)sub-optimal.

[0270] Liquid-containing squeeze bottles dispense atomized liquid uponpressurization of the bottle effected by squeezing. However, the amountof liquid expelled upon squeezing, the direction in which the liquid isexpelled, and the velocity at which it is expelled can vary quiteconsiderably based on how the user manipulates the device. Furthermore,the degree of atomization (i.e., the size of the droplets) may depend onthe force applied to the container.

[0271] Liquid-containing manual pump-type containers dispense atomizedliquid upon actuation by the user of a pump mechanism, in whichdisplacement of a portion of the container along a vertical axis of thecontainer causes atomized liquid to be expelled from a second portion ofthe container, generally in a direction parallel to the longitudinalaxis of the container. By inserting the second portion into a nostriland actuating the pump, a stream or mist of atomized liquid is expelledinto the nostril. These devices, like the other prior art devices,exhibit significant variability in the direction in which the liquid isexpelled, owing to variation in the positioning of the device by theuser. Furthermore, because these devices are operated by applyingpressure to the device in a direction toward the interior of thenostril, these devices are uncomfortable and present the possibility ofinjury due to accidental excessive applied force or misplacement by thedistressed user.

[0272] Liquid-containing pressurized containers dispense atomized liquidupon manipulation by the patient of a triggering mechanism. For example,many such devices comprise a valve through which atomized or liquidmedication is expelled upon depressing a trigger or other actuator toopen the valve. Although these containers may exhibit improved controlover the amount and velocity of expelled fluid, relative to squeezebottles, the intranasal direction in which the liquid is delivereddepends heavily on actions of the user.

[0273] Droppers, pipettes, and other bulk liquid instillation devicesshare the drawback that either the patient must remain in an awkwardposition (e.g., lying on the back, with the head propped up and to oneside) in order to retain the liquid in the nasal cavity for anappreciable period or, alternatively, that administration must berepeated numerous times, owing to rapid drainage of the liquid from thenasal cavity. In addition, instillation of bulk liquid into the nasalcavity presents the risk that the liquid will be inhaled by the patientinto the lungs or passed through the nasopharynx into the esophagus anddigestive system. This increases uncomfortable numbness and potentiallycompromises protective airway and swallowing reflexes. Furthermore,increased wastage leads to increased systemic levels of drug anddecreased desired local effects.

[0274] Microfine powder dispersers and nebulizers may be used to deliverpowders and atomized liquids, respectively, to the nasal epithelium, butshare a number of drawbacks. First of all, the pattern of delivery willlargely parallel the pattern of inhalative air flow through the nasalcavity, and therefore may not distribute the agent evenly to the nasalepithelium, particularly to more remote regions, such as the dorsonasalregion or a superior portion of the nasal epithelium. Second of all, asignificant portion of inhaled powder and mist bypasses the nasalepithelium altogether, and instead is carried, along with bulk inhaledair, into the bronchi and lungs. When systemic delivery of a compound isdesired, such bypass may be desirable. However, when local directedintranasal (e.g., dorsonasal) administration is desired, this bypass mayfrustrate effective delivery.

[0275] All of these prior art drug delivery devices share a commonshortcoming. Each disperses the drug non-specifically to the nasalepithelium and does not target local areas such as those overlying anerve structure (e.g., a portion of the nasal epithelium including oroverlying a branch of an InNS such as the olfactory nerve or anotherDnNS such as the SPG, a ciliary blood vessel, or ciliary nerve), thoseoverlying an intranasal blood vessel, or the nasal cavity orifices ofthe sinuses.

[0276] The shortcomings of the prior art drug delivery devices may beunderstood in view of the fact that directed administration ofcompositions to selected remote areas of the nasal epithelium (e.g., thedorsonasal region or a superior portion of the nasal epithelium) has notpreviously been demonstrated. Prior art intranasal drug delivery methodshave generally taught administration to the largest possible portion ofthe intranasal epithelium, in order to provide the drug to much of theintranasal epithelium. In contrast, as described herein, several of themethods of the invention teach that dorsonasal, or otherintranasally-targeted, administration of a pharmaceutical composition(e.g., a composition comprising a long-acting local anesthetic) may bepreferable for a number of reasons. For example, in one embodiment, themethod of inhibiting a cerebral neurovascular disorder described hereininvolves dorsonasally administering a long-acting local anestheticpharmaceutical composition to a human. Intranasal administration ofcompositions to portions of the nasal epithelium overlying an InNS or anInBV can deliver a pharmaceutically-active (i.e.,pharmacologically-active or biologically-active) agent to the InNS orInBV, or to another tissue that communicates therewith. For example,intranasal administration of a composition to a portion of the nasalepithelium overlying an InBV can be used to effect systemicadminstration (or local vascular delivery) of the agent, and intranasaladministration of a composition to a portion of the nasal epitheliumoverlying an InNS can be used to effect delivery of the agent to anothernerve structure (e.g., a cephalic ganglion, the spinal cord, or aportion of the brain) with which the InNS connects.

[0277] First, it is believed that the site at which long-acting localanesthetics have their biological effect may be physically located at orin close proximity to the portion of the nasal epithelium to which anintranasally administered composition is applied (i.e., as describedelsewhere herein, for example, to the region of the nasal epitheliumoverlying the SPG for a dorsonasally administered local anesthetic);thus, dorsonasal administration may be preferable to general intranasaladministration because it directs the pharmaceutically active agent toor near its site of action for treatment of migraine and headache.

[0278] Second, site-directed (e.g., dorsonasal) administration may beused to intentionally limit intranasal delivery of the biologicallyactive agent to non-desired intranasal sites, thereby minimizing uptakeof the biologically active agent into the bloodstream. This may beparticularly important with biologically active agents (e.g.,dextro-bupivacaine) which, at high bloodstream concentrations of theagent, have undesirable side-effects are used.

[0279] Third, because directed intranasal administration limits uptakeof the administered agent into the bloodstream, the agent may bedelivered (e.g., to a dorsonasal nerve structure) more frequently and ata higher concentration or greater amount than it could if it wereadministered in a more anatomically diffuse way. Therefore, highconcentrations of the agent may be achieved in a tissue (e.g., the SPG,cerebro-spinal fluid, or a brain or other CNS structure) located at orin close proximity to the dorsonasal epithelium. When the agent has abiological activity which decreases over time (e.g., a localanesthetic), administration of a high local concentration of the agentmay prolong the duration of the intended biological effect.

[0280] Fourth, with intranasal administration of a compound having anuncomfortable, but non-harmful, side-effect (e.g., numbness), it may bepreferable to limit the exposure to the compound to the type or theamount of tissue which exhibits the side effect by administering thecompound only, or preferentially, to a selected portion of the nasalepithelium (e.g., dorsonasally), thereby limiting the side-effect uponnon-targeted tissues.

[0281] Other advantages of directed intranasal administration, incontrast to general intranasal administration will also be understood bythe skilled artisan in view of the present disclosure.

[0282] With reference to FIGS. 4A, 4B, and 4C, the invention includes anintranasal drug delivery device or applicator which comprises a body100, preferably a generally elongate body such as a swab or a tube,which has a shape which conforms to the shape of the nasal cavity andhas distal portion having a distal end 103. The distal portion of theelongate body may be inserted into the apex A of the nasal cavity, asillustrated in FIG. 4, without injuring the patient. The apex of thenasal cavity is the superior and posterior portion of the nasal cavitywhich lies posterior to the nasal septum and anterior to thesphenoethmoidal recess. The apex of the nasal cavity communicates witheach of the nostrils, and the inferior IC, middle MC, and superior nasalconchae SC are situated in the passage from each nostril N to the apex.The elongate body may be substantially rigid or flexible, and ispreferably flexible, in order to facilitate placement of the distalportion thereof in the apex of the nasal cavity.

[0283] When not inserted into the nasal cavity, the elongate body mayhave a generally curved or angled shape, wherein the longitudinal axisof the elongate body is angled at the distal end, with respect to thelongitudinal axis at the proximal end. Preferably the angle defined bythe intersection of the longitudinal axis at the distal end and thelongitudinal axis at the proximal end is about 90 and about 170 degrees,more preferably about 110 and about 160 degrees or about 120 and about150 degrees. The elongate body may be flexible along its entire length,or it may comprise one or more flexible or hinged sections, whereby thelongitudinal axis of the distal end of the body may be deflected fromthe longitudinal axis at the proximal end.

[0284] In an alternative embodiment, the body is elongated, has an ovalcross-section, is substantially straight, and has a lumen extendingtherethrough from the proximal end to the distal end. When the body isinserted into the nasal cavity, the distal end of the body extends abovethe nasal conchae, and the outlet port (i.e., at the distal end of thelumen) is positioned on the body such that the composition expelled fromthe outlet port is directed within the nasal cavity toward a selectedsurface of the nasal cavity, thus effecting directed intranasaladministration of the composition. For example, the device can have oneor more outlet ports that are positioned on the device such that whenthe device is inserted into the apex of the nasal cavity, a compositioncan be delivered through the lumen of the device dorsonasally, to asuperior portion of the nasal epithelium, or both. The device canalternatively be used to direct administration of the composition to oneor more other portions of the nasal cavity.

[0285] The shape of the intranasal delivery device may be envisioned asfollows. It is preferably in the form of an elongate solid or hollowbody, such as a tube, a flattened rod, or the like, that may beenvisioned as lying on a plane surface. The body is bent or curved alongthe surface of the plane, either at one point, at several points alongits length, or over its entire length, such that the longitudinal axisof the elongate body is angled at the distal end, with respect to thelongitudinal axis at the proximal end, as described above. The bodythereafter has a shape which conforms to the shape of a human nasalcavity. Optionally, the body may be further curved, again at one point,a plurality of points, or along its entire length, such that the distalend of the body is angled at an oblique angle with respect to the planewhen the proximal end of the body is maintained in the plane.

[0286] One or more sections of the elongate body may be curved tofacilitate insertion of the body past the nasal conchae, or to conformthe shape of the body to the shape of the nasal cavity, in order thatthe body may rest more securely and comfortably in the nasal cavityafter insertion.

[0287] With reference to FIGS. 4A-4K, the body 100, illustrated as thepreferred elongate body, may have one or more lumens 101 extending fromthe proximal end thereof to one or more outlet ports 102 extending fromthe lumen to the exterior of the elongate body. The elongate body mayhave a substantially circular cross-section, an oval or flattenedcircular cross-section, a rounded rectangular cross section, a squarecross-section, or substantially any other cross-sectional shape which isaccommodated by the nostrils and nasal cavity of a human. The elongatebody may have an indicium or indicia thereon or therein which indicateto the user the orientation of the distal end of the body with respectto the longitudinal axis of the body at the proximal end thereof.Alternatively, the proximal end of the body may have a curved portionhaving a fixed relationship with the distal end, whereby the orientationof the distal end of the body may be determined. Thus, a user candetermine the orientation of the distal end 103 of the body 100 when itis emplaced within the nasal cavity of a patient by observing theposition of the indicia 105 at the proximal end of the body. This mayassist proper placement of the distal end of the applicator in the apexof the nasal cavity of the patient.

[0288] The outlet ports 102 may be located at the distal end 103 of thebody 100 (i.e., as in FIGS. 4A and 4B), along the distal portion of thebody (i.e., as in FIG. 4C), between the proximal and distal ends (i.e.,as in FIG. 4D), or some combination thereof. Outlet ports may also belocated substantially at one peripheral location relative to theelongate body (e.g., all on one side of a flattened elongate body), orthey may be peripherally distributed around the perimeter of the body.The outlet ports may have any shape (e.g., round, square, a slit, etc.).One or more of the outlet ports may also be situated on the elongatebody such that it will be occluded when the elongate body is placedwithin the nasal cavity of a patient. The body 100 may comprise aplurality of lumens 101, wherein certain outlet ports 102 communicatewith one lumen, while others communicate with another lumen. Using sucha device, a plurality of compositions may be administered to differentsites within the nasal cavity. By way of example, the body may have afirst lumen which communicates with a first set of outlet ports fordorsonasally administering a first composition to a patient and a secondlumen which communicates with a second set of outlet ports foradministering a second composition specifically to the nasal conchae orto a superior portion of the nasal epithelium. By administering thecomposition to one or more highly vascularized portions of the nasalepithelium or to a portion of the nasal epithelium overlying an InBV,the composition may be systemically administered to the patient.

[0289] The lumen(s) may be connected to a fluid-, gel-, orpowder-containing reservoir, or a needle, probe, tube, or other elongateinstrument 110 may be threaded through the lumen and, optionally,extended out of an outlet port 102. For example, the elongate instrument110 can be maintained in a compressed state within the body 100 of thedevice during insertion of the device into a nostril, and can beexpanded thereafter (e.g., upon engorgement with liquid agent provided,for example by way of the lumen 101, as illustrated in FIG. 4M). Invarious embodiments the elongate instrument may include a swab, rosette,balloon, etc. which is impregnated or coated with a pharmaceuticallyactive composition and which is extended or inflated from the lumenthrough the outlet port following placement of the distal end of theelongate body in the apex of the nasal cavity (i.e., as in FIGS. 4F, 4G,and 4H). Such an extendable or inflatable elongate instrument 110 mayoptionally be retractable or deflatable. When the elongate instrument110 is inflatable, it may be positioned on the device in such a way thatit deflects a portion of the device upon inflation, as illustrated inFIG. 4G. An elongate instrument 110 can be tapered, as illustrated inFIG. 4N, to facilitate comfortable and minimally traumatic removal ofthe device from the subject's nostril. The elongate instrument may alsobe a solid or hollow needle which is coated with or which facilitatesdelivery of a pharmaceutically active composition (e.g., a localanesthetic) to a tissue located near the distal end of the elongate body(or near an outlet port 102) after placement of that distal end 103 inthe apex of the nasal cavity. The hollow needle may be either sheathedor non-sheathed, and may, for example, either contain or communicatewith a reservoir which contains a pharmaceutically active composition.

[0290] In one embodiment of the device/applicator, the elongate body hasan angled shape, as illustrated in FIGS. 4J and 4K, an oval crosssection, and two lumens 101 extending longitudinally therethrough fromthe proximal end to each of a pair of outlet ports located on the distalportion thereof. The two outlet ports are located on opposite faces ofthe distal portion of the body. The body has a shape which conforms tothe shape of the nasal cavity on either side of the nasal septum.Therefore, this body may be inserted into either nostril of the patientin order to administer a composition dorsonasally to the patient.Furthermore, this embodiment of the applicator may further comprise aswitching mechanism which permits the patient to select one of the twolumens for delivery of the composition, depending on the nostril intowhich the device is to be inserted. The switching mechanism may beassociated with an excluder mechanism which blocks or inhibits insertionof the device into the non-selected nostril. Such an excluder mechanismmay, for example, be an arm which is located beside the patient's noseon the side of the selected nostril when the device is inserted into theselected nostril, but which contacts the selected nostril in the eventthe patient attempts to insert the device into the non-selected nostril.

[0291] In another embodiment of this applicator, the body has one ormore fibers embedded therein or passing through a lumen extendingtherethrough, whereby each fiber is fixed to the distal portion of thebody and extends through the proximal end of the body. By pulling ortwisting on a fiber, the pulling or twisting force may be imparted tothe distal end of the body, thereby permitting the distal end to be“steered” to some degree by manipulation of the fiber(s).

[0292] A pharmaceutical composition may be delivered to a tissue (e.g.,the SPG or a tissue overlying it) located near the distal end 103 of thebody 100 after placement of that distal end in the apex of the nasalcavity either by providing the composition through a lumen 101 in theelongate body, as described above, or by applying the compositiondirectly using the body. A pharmaceutical composition can also bedelivered to tissues that are near an outlet port 102 when the device isemplaced in the nasal cavity (e.g., to the superior surface of the nasalcavity and to the upper face of the superior concha using the deviceshown in FIG. 4D). The applicator portion of the elongate body may bedipped in, constructed of, impregnated with, or coated with acomposition comprising the pharmaceutical composition. Furthermore, theapplicator portion may be in fluid communication (e.g., by way of alumen 101 extending within the body 100) with a reservoir containing thepharmaceutical composition, whereby the composition may be provided fromthe reservoir to the applicator portion. For example, in the embodimentof the applicator depicted in FIG. 4L, a reservoir 114 is attached (orattachable, e.g., via a collar 116) to the body 100 such that a lumen101 which extends through the body 100 places the contents of thereservoir 114 in fluid communication with an absorbent portion 112associated with (e.g., attached to, initially compressed within, orboth) the opposite end of the body 100. Thus, the contents of thereservoir 114 can be absorbed by the absorbent portion 112, for exampleupon inverting the device or upon squeezing the reservoir 114. Directcontact of the applicator portion of the elongate body and a portion ofthe nasal epithelium situated in the apex of the nasal cavity transfersthe composition from the body to the epithelium. The body may also beconstructed of, or have a portion comprising, an absorbent material 104.The distal end 103 of the body 100 is preferably smooth or rounded, andmay optionally have a smooth or rounded member 106 attached thereto.

[0293] Alternatively, at least the distal end of the elongate body mayhave a layer of a pharmaceutical composition situated between the bodyand a retractable or degradable sheath which covers it. The sheath may,for example, be retracted by sliding the sheath proximally along theexterior of the elongate body, or by drawing the sheath into or througha lumen extending within the elongate body. Retraction or degradation ofthe sheath exposes the pharmaceutical composition, which may then beapplied directly to a selected portion of the nasal epithelium, such asa portion overlying the SPG or a portion that includes or overlies oneor more branches of the olfactory nerve or another InNS or an InBV. Thedegradable sheath may, for example, be made of a material which degradesshortly following contact with moisture. Thus, by inserting a bodyhaving an applicator portion covered with such a degradable sheath intothe apex of the nasal cavity of a patient, degradation of the sheath iseffected and causes the composition on the applicator portion to beexposed, whereupon it may be applied to a portion of the nasalepithelium.

[0294] The invention further includes a systemic drug delivery devicewhich has the same construction as the intranasal delivery device of theinvention, except that the device has an applicator portion, which may,for example, be a portion on which the drug is present, a portion towhich the drug may be supplied, or a lumen through which the drug may besupplied. This applicator portion is preferably adapted for location inclose anatomic proximity to a highly vascularized portion of the nasalepithelium when the distal portion of the body of the device is in theapex of the nasal cavity. Such a device may, for example, have anabsorbent portion in which the drug is absorbed and which contacts oneor more of the nasal conchae when the device is placed in the nasalcavity. Alternatively, the device may have a lumen which communicateswith an outlet port which is situated on the device such that the portis opposite a desired anatomic site (e.g., a nasal concha or the nasalorifice of a sinus) when the device is placed in the nasal cavity.

[0295] The invention also includes an anatomically adapted intranasaldelivery nozzle 200 which may be used as an applicator for providing agel, foam, vaporized, aerosolized, or atomized liquid, or a dispersedpowder or micropowder to or near the apex of the nasal cavity, whilepreferably minimizing delivery of the composition to other portions ofthe nasal cavity. One embodiment of such a nozzle is illustrated inFIGS. 5 and 6. The nozzle has a body having one or more delivery lumens201, each of which extends through the nozzle from the proximal end 210thereof to one or more outlet ports 202 located on the distal portion203 thereof. The nozzle has an exterior portion which is shaped asfollows. The exterior portion has a flattened portion 204 situatedbetween the proximal end 210 and the distal portion 203 thereof forseating against the nasal septum. The exterior portion also has ananterior portion 206 situated between the proximal end 210 and thedistal portion 203 thereof for seating against at least one portion ofthe nasal cartilage. The exterior portion also has a posterior portionhaving one or more indentations 208 situated between the proximal end210 and the distal portion 203 thereof for seating against one or moreof the nasal conchae. Each indention has a generally curved shape whichconforms to the shape of the corresponding nasal concha. For example,the exterior portion may have a distal and a proximal indentation, thedistal indentation being located nearer the distal end of the nozzle,wherein the distal indentation is adapted to the shape of the middleconcha for seating the nozzle against the middle concha, and wherein theproximal indentation is adapted to the shape of the inferior concha forseating the nozzle against the inferior concha.

[0296] The delivery lumen 201 of the anatomically adapted intranasaldelivery nozzle extends from the proximal end 210 of the nozzle to adischarge port 202 at the distal end 203 thereof. When the nozzle isseated in the nasal cavity of a human, the discharge port is situatedsuch that the axis extending (generally perpendicularly) through thedischarge port passes through the apex of the nasal cavity, or is offsetfrom the apex of the nasal cavity by an angle, phi, as indicated in FIG.6, such that phi is from 0 to about 30 degrees, and preferably such thatphi is from 0 to about 15 degrees. The discharge port may be generallycircular, or it may be shaped (e.g., oval, or circular having opposedraised portions on the circumference thereof) in order to morespecifically direct the composition discharged therethrough at aselected portion of the nasal epithelium (e.g., a portion situated inthe sphenoethmoidal recess). The proximal end of the anatomicallyadapted dorsonasal delivery nozzle may be connected with one or morereservoirs, generators, or other sources of the agent, or a combinationof agents, to be delivered therethrough. A single source of agent may bedirected through a plurality of delivery lumens which connect the sourcewith one or a plurality of discharge ports. Alternatively, independentsources of different agents may be directed through a plurality ofdelivery lumens which connect the sources with one or a plurality ofdischarge ports.

[0297] The anatomically adapted intranasal delivery nozzle may beconstructed of a rigid, flexible, deformable, or elastomeric material.In one embodiment, the nozzle is constructed of a material which is,either initially or under certain conditions (e.g., above a certaintemperature), deformable. Such a material may, for example, be a wax ora plastic which becomes pliable when heated to a temperature abovenormal body temperature (i.e., >about 98° F.), but below a temperaturewhich will cause injury to human nasal epithelium upon contact therewithfor several minutes (i.e., <about 108° F.). Other exemplary materialsare plastic composition which either remains plastic (e.g., a closedcell foam) or are which hardens with time (e.g., a polymerizingplastic). According to this latter embodiment, the nozzle is insertedinto a nostril of the patient who will thereafter use the nozzle, inorder to conform the nozzle to the interior geometry of that patient'snasal cavity. This procedure is preferably performed by a medicalpractitioner, or by a person having knowledge of the anatomy of thehuman nasal cavity, so that the nozzle is seated in the patient'snostril such that the discharge outlet is directed toward the apex ofthe patient's nasal cavity (i.e., the angle phi in FIG. 6 is from 0 toabout 30 degrees). Alternatively, a deformable material may be insertedinto a patient's nasal cavity in order to record the shape thereof, andthis deformed material may subsequently be used to fashion a mold forduplicating that shape.

[0298] The anatomically adapted dorsonasal delivery nozzle mayoptionally further comprise one or more distal seating portion which,upon insertion of the nozzle into the nostril of the patient, contactthe superior surface of the nasal cavity, thereby preventingover-insertion of the nozzle. The discharge port(s) may be inferiorlyspaced with respect to the distal seating portion when it is seatedwithin the nasal cavity of the patient, so that the path between thedischarge port and the apex of the nasal cavity is not blocked by theconchae.

[0299] The anatomically adapted intranasal delivery nozzle is used todeliver a composition intranasal by seating the nozzle in a nostril of apatient, such that the flattened portion is seated against the nasalseptum, the indentation, if any, is seated against a concha, and theanterior portion is seated against the nasal cartilage. Optionally, orin place of one of these other seatings, the distal seating portion isseated against the superior surface of the nasal cavity. When the nozzleis thus seated, a gel, foam, mousse, liquid, dispersed power, aerosol,etc. comprising the composition is provided to the delivery lumen,thence to the discharge port, and thence into the nasal cavity of thepatient (e.g., to a dorsonasal or superior portion of the nasalepithelium). In the apex, the composition can contact a dorsonasallylocated portion of the nasal epithelium and thereby deliver thecomposition to that portion. It is noted that certain anatomicallyadapted intranasal delivery nozzles may be adapted for only one nostrilof the patient; when this is so, a second nozzle adapted for the othernostril of the same patient should be provided. Alternatively, theoutlet port of the nozzle may be changeable (i.e., rotatable ordeflectable), such that the same adapter portion, with the outlet portfacing in the opposite direction, may be used in the patient's othernostril.

[0300] The anatomically adapted delivery nozzle of the invention may beadapted, by placing the outlet port thereof at an alternative locationon the body of the nozzle, to deliver a composition specifically to adifferent portion of the nasal cavity, such as to the nasal cavityorifice of one or more sinuses. The composition thus delivered may, forexample, be a pharmaceutical composition comprising one or both of asteroid and a vasoconstrictor. By specifically delivering such acomposition to the anatomical site at which it exerts its biologicalactivity, the amount of drug which is administered may be minimized andside effects normally associated with administration of the composition(e.g., nasal epithelial hypertrophy associated with intranasaladministration of vasoconstrictors) may be minimized.

[0301] The invention also includes an intranasal drug delivery device orapplicator which overcomes a particular shortcoming of prior artintranasal drug delivery devices. As illustrated in FIG. 7A, prior artintranasal drug delivery devices are actuated by applying pressure toall or a portion of the applicator in a direction that is substantiallyco-linear (i.e., not more than about 15 degrees offset from co-linear)from the axis of the nostril. Use of such devices carries the risk thatthe device may be unintentionally urged, along the axis of the nostril,with excessive force, leading to discomfort or injury of the patient.

[0302] The improved intranasal drug delivery device 300 of the inventionovercomes this limitation by changing the direction in which pressure isapplied to the device by the patient. As illustrated in FIGS. 7B and 7C,the improved intranasal delivery device comprises an intranostrilapplicator 302 having a lumen extending therethrough. The lumen of theintranostril applicator is in fluid communication with a discharge porton an end of the intranostril applicator, which is insertable within anostril of a human patient. This lumen is also in actuatable fluidcommunication with a drug within a container 304. Fluid communicationbetween the lumen and the interior of the container is actuated byapplication of force by the patient to an actuator interposed betweenthe lumen and the interior of the container. When the patient appliesforce to the actuator, the drug is provided to the lumen of theintranostril applicator, thence through the discharge port and into thenasal cavity of the patient.

[0303] The intranostril applicator may be substantially any body whichmay be inserted fully or partially into the nostril of a human and whichhas a lumen extending therethrough. The drug container may besubstantially any container which is pressure-activated, such as apressurized drug container connected to the lumen of the intranostrilapplicator by a manual pressure-actuated valve, a pressure-activatedpump, a syringe, a metered dose applicator, and the like. Preferably,the intranostril applicator and at least a portion of the drug containerare of a unitary construction. Alternatively, the intranostrilapplicator and the drug container may be detachable, whereby theintranostril applicator may be inserted into a nostril of a patientprior to attaching the drug container thereto.

[0304] An important feature of the improved intranasal drug deliverydevice of the invention is that the pressure which is applied by thepatient in order to actuate the same is applied at an angle offset from(i.e., at least about 15 degrees offset from, and preferably about 30,about 45, about 60, or about 90 degrees offset from) the axis of thenostril in which the intranostril applicator is placed. The discomfortand the risk of injury to the patient due to inappropriate drug sourceactuation pressure is thereby reduced significantly, and the device isalso made easier to use. Any inappropriate pressure is likely to causethe intranostril applicator to twist within or become disengaged fromthe nostril, rather than cause the intranostril applicator to be drivenalong the axis of the nostril into a tissue, which would injure thepatient.

[0305] The invention also includes a dorsonasally implanted electronicneural stimulator, such as a transepithelial neural stimulation (TENS)device. This device is implanted anatomically close to, preferably incontact with, a dorsonasal nerve structure such as the SPG. The devicemay, for example, be implanted on or in the dorsonasal epithelium, suchas a portion of the nasal epithelium overlying a dorsonasal nervestructure. The device may be mono- or bi-polar. The device may have aninternal power supply, or power may be supplied to the device using anexternal device (e.g., an inductively coupled power supply). Nerve blockof a dorsonasal nerve structure may thus be effected by energizing thedevice, meaning that electrical potential is provided to the device,such as from an internal power supply, external power supply leads, orfrom an extra-corporeal inductively coupled power supply.

[0306] The Kit of the Invention

[0307] The invention additionally includes a kit comprising along-acting local anesthetic pharmaceutical composition, as describedherein, and an applicator, as also described herein, for intranasally,and preferably dorsonasally, administering the composition to a humanpatient to inhibit a CNvD. The kit is used by administering thecomposition to the patient at a time when the patient is experiencing asymptom of a CNvD episode or a prodromal symptom of a CNvD. The kit mayfurther comprise a migraine therapeutic pharmaceutical agent, anotherpharmaceutically active agent, another local anesthetic, and the like.The kit may, and preferably does, further comprise instructionalmaterial which describes directed intranasal (e.g., dorsonasal)administration of the composition to a patient. The instructionalmaterial may, for example, comprise written instructions to intranasallyor dorsonasally administer the composition included in the kit inaccordance with this invention.

[0308] The kit described herein may also be used for inhibition ofmuscular headaches. The components of the kit for this purpose aresubstantially the same, with the exception that any instructionalmaterial should describe the usefulness of the compositions and methodsof the invention for inhibiting a muscular headache, rather than, or inaddition to, a CNvD. If the kit may also be used to inhibit a muscularheadache, in which instance the local anesthetic pharmaceuticalcomposition need not be long-acting and is administered to the patientduring a muscular headache episode.

[0309] Co-Administration of a Local Anesthetic and Another Compound toEffect Systemic Delivery of the Compound

[0310] The invention further relates to the discovery thatnon-intravenous administration of a composition comprising a localanesthetic and a pharmaceutically active agent to an animal such as amammal, particularly a human, improves systemic uptake of the agent inthe animal, relative to the uptake achieved by non-intravenousadministration of the agent alone to the animal by the same route.

[0311] The present invention includes a method of systemic drugdelivery, the method comprising non-intravenously administering to ahuman patient a composition comprising a local anesthetic and apharmaceutically active agent, whereby systemic delivery of the agent isimproved relative to systemic delivery of the agent when delivered bythe same non-intravenous route in the absence of the local anesthetic.The pharmaceutically active agent may be any drug. It is contemplatedthat this method of effecting systemic delivery is particularly usefulfor delivery of any agent which is able to diffuse through vascular andother tissues to a greater degree in the presence of the localanesthetic than in the absence of the local anesthetic. Thus, the agentmay be, for example, a hormone, a peptide, a liposome, or a polymericmolecule such as heparin.

[0312] Any pharmaceutically active agent which is desired to bedelivered systemically may be co-administered non-intravenously in acomposition comprising the agent and a local anesthetic. Where the localanesthetic is not being administered for the purpose of inhibiting aCNvD, delivery of a composition comprising a local anesthetic and theagent intended for systemic delivery need not be directed to thedorsonasal region of the nasal cavity. Because the nasal cavity ishighly vascularized, delivery of the composition may be directed tosubstantially any portion of the nasal epithelium to achieve systemicdelivery of the agent. Furthermore, the composition may be delivered toany vascularized tissue, such as to the surface of a mucosal epitheliumor to a skin surface, for example, to achieve systemic delivery of theagent.

[0313] The local anesthetic may be any local anesthetic except cocaine,which is a vasoconstrictor. The local anesthetic compounds,formulations, dosages, and methods of administration which are usefulfor this method of the invention are substantially the same as thosedescribed herein with respect to inhibiting a neurovascular headache, amuscular headache, or a CNvD. Compounds, formulations, and dosages ofthe other pharmaceutically active agents described in this method areknown in the art. Owing, in part, to the vasodilatory activity of localanesthetics, these compounds may be used according to this method atdoses of about half their art-recognized doses to their fullart-recognized doses.

[0314] Theory Proposed to Explain the Mechanism of Improved SystemicDelivery of a Pharmaceutically Active Agent by Co-Administration with aLocal Anesthetic

[0315] Without wishing to be bound by any particular theory, it isbelieved that administration of a local anesthetic to a vascularizedtissue induces dilation of blood vessels within the tissue. Vasodilationresults in recruitment of surface blood vessels and increases theability of a compound present in the tissue to pass into the systemiccirculation. Similarly, carrier preparations (e.g., DMSO, proteins,peptides, and/or charged compounds) can facilitate delivery of thecomposition to an InNS or InBV to effect systemic or CNS delivery of thecomposition. Therefore, co-administration to a tissue of a localanesthetic and a pharmaceutically active agent improves the ability ofthe agent to pass from the tissue to the bloodstream for systemicdelivery.

[0316] Dosing Information Relevant to Systemic Drug Delivery

[0317] The local anesthetic doses and formulations which are useful forco-administration of the local anesthetic and another compound to effectsystemic delivery of the compound are substantially the same as thosedescribed for the method of inhibiting a CNvD. In view of the presentdisclosure, it will be understood by the artisan of ordinary skill thatthe dose and formulation of the local anesthetic will depend upon, amongother factors, the age, size, condition, and state of health of theanimal, the anatomical location to which the composition will bedelivered, the identity of the local anesthetic, and the identity of thecompound to be co-administered. Substantially any amount of localanesthetic may be used. By way of example, compositions which comprisethe compound to be co-administered and the local anesthetic at aconcentration of about 0.01% to about 53% by weight, and preferablyabout 0.25% to about 10% by weight, more preferably about 0.5% to about5% by weight, and most preferably about 2.5% by weight, may be used. Thecomposition may be prepared as a liquid, a semi-solid, or a solid, asdescribed herein. The composition may be formulated for intranasal,topical, subcutaneous, buccal, or substantially any othernon-intravenous route of administration using methods and compositionswell known in the art. The dose of the compound to be co-administered isdependent upon the identity of the compound, the purpose for which thecompound is to be administered, and the size, age, condition, and stateof health of the animal. Compounds, formulations, and dosages ofpharmaceutically active agents described in this method are known in theart. Owing, in part, to the vasodilatory activity of local anesthetics,these compounds may be used according to this method at doses of abouthalf their art-recognized doses to their full art-recognized doses.

[0318] While the invention has been described with reference to humananatomy, it is contemplated that the compositions and methods of theinvention can be used analogously in any animal, particularly in anymammal, especially regarding co-administration of a local anesthetic andany pharmaceutically active agent to effect or enhance systemic deliveryof the agent.

[0319] Directed Intranasal Adminstration of a Pharmaceutical Composition

[0320] Intranasal administration of a pharmaceutical compositiondirected to only a portion of the nasal epithelium of a patient canavoid drawbacks of previous non-directed intranasal delivery methods.For example, administration can be directed specifically to a portion ofthe nasal epithelium that overlies (or is in close proximity to) an InNSor an InBV. For compositions (e.g., local anesthetics and compoundsco-administered with a local anesthetic) that are capable of diffusingthrough epithelial tissue, directing administration to a portion of theepithelium located in close anatomical proximity to the InNS or InBV canresult in delivery of the composition to the selected InNS or InBV.

[0321] When delivery of a composition to the olfactory nerve (or thenceto the olfactory bulb or the brain) is desired, the composition shouldbe administered to the superior surface of the nasal cavity, where thebranches of the olfactory nerve that penetrate the cribiform plate ofthe ethmoid bone and emerge at or near the surface of the nasalepithelium. At least some extensions of the olfactory nerve emerge fromthe ethmoid into the superior nasal concha and the upper portion of thenasal septum. The dorsonasal portion of the nasal epithelium can alsoinclude branches of the olfactory nerve, although innervation variesamong individuals Directed intranasal delivery of a composition to anerve structure such as the olfactory nerve demonstrates that intranasaladministration of a composition, if directed to an appropriateintranasal tissue or structure, can result in uptake of an active agentby a nerve structure that is separated from the nasal cavity by a bone(e.g., the olfactory nerve is separated from the nasal cavity by thecribiform plate of the ethmoid bone as well as the nasal epithelium).

[0322] Portions of at least the olfactory, nasal, ethmoidal, palatine,greater petrosal, and maxillary nerves are located in close anatomicalproximity to portions of the nasal epithelium, and compositions having asufficiently high ability to diffuse through nasal epithelium tissue canbe delivered to these nerves by way of intranasal administration to thecorresponding portion of the nasal epithelium.

[0323] The identity of the active agent in the composition administeredto an InNS or an InBV is not critical, so long as the composition isadministered to a portion of the nasal epithelium overlying or insufficiently close proximity to the InNS or InBV and in a carrier orwith a compound (e.g., a local anesthetic, lipid carrier, or othertissue-penetrance-modulating preparation) that facilitates diffusion orother transport of the agent to the InNS or InBV. Non-limiting examplesof useful agents include natural or altered or carrier viruses, prions,other infectious or therapeutic cellular or subcellular agents ormicroorganisms, stem cells, or other cellular therapeutic agents, DNA,RNA, oligonucleotides, polypeptides, amino acids, fatty acids, lipids,carbohydrates, vitamins, supplements, minerals, nutrients, oxygenatedsubstrates, microspheres, antibiotics, antiviral agents, antifungalagents, memory enhancing agents, neurotransmitters, antiepileptics,antiseizure agents, analgesics, ions including magnesium,anti-neuropathic pain agents, anti-central pain agents, antidepressantagents, cox inhibitors (including cox2 inhibitors), LOX inhibitors,membrane stabilizing agents, growth factors, hormones (e.g., anabolicand catabolic steroids), ATP, ADP, NAD(P), NAD(P)H, energy substrates,propylene glycol, carrier molecules, DMSO, cytokines, anti-cytokines,TNF, anti-inflammatory agents, melatonin, chemotherapy agents, andradiolabeled compounds.

[0324] In one embodiment, intranasal delivery of a compositioncontaining an active agent is performed as described herein. Thecomposition is administered to a portion of the nasal epithelium thatoverlies an InNS. The composition is administered in a sufficiently highamount that the agent is not only taken up by the InNS, but is alsodelivered to another nerve structure with which the InNS communicates.In one example, a composition is administered to a superior portion ofthe nasal cavity in order to effect delivery of an agent to theolfactory nerve. By way of the olfactory nerve, the agent travels (e.g.,diffuses or is actively transported) to the olfactory bulb of the brain(i.e., with which the olfactory nerve connects) and thence to the brain.In another example, a composition comprising an agent is dorsonasallyadministered so that the agent is taken up by a DnNS (e.g., the SPG) andtransported to another nerve structure with which the DnNS is connected(e.g., the SPG is connected to the trigeminal nerve and, by way thereof,to the brain). In this way, cephalic, spinal cord, or other neuraldelivery of the agent can be effected. Similar methods can be used todirect administration of the composition to other portions of the nasalcavity so as to effect delivery to selected InNSs, selected InBVs, andtissues in which the two are intimately related.

[0325] The dose of agent that should be used in the intranasal deliverymethods described herein depends on the identity of the agent and theidentity of the targeted tissue. When compositions are directed to aportion of the nasal cavity including or overlying an InNS in order toeffect delivery of the composition (or a component of the composition)to the central nervous system (CNS), the dose of the agent in thecomposition can often be significantly lower than the dose that would benecessary to administer by an oral or intravenous route. When systemicdelivery of an agent is desired, directed delivery of a compositioncomprising a high concentration of the agent can be used, so as toenhance the rate and amount of agent taken up into the bloodstream.Thus, agents delivered by directed intranasal administration can beadministered in concentrations and amounts ranging from at least severaltimes the amount administered orally or intravenously to amounts assmall as 1% to 10% the amount administered orally or intravenously,depending on the agent. A skilled artisan is able to titrate amountsappropriately, for example administering a small amount at first andgradually increasing the dosage until a desired pharmacological effectis achieved.

[0326] The invention is now described with reference to the followingExamples. These Examples are provided for the purpose of illustrationonly and the invention should in no way be construed as being limited tothese Examples, but rather, should be construed to encompass any and allvariations which become evident as a result of the teaching providedherein.

EXAMPLE 1

[0327] Dorsonasal Administration of Ropivacaine for Inhibition of AcuteMigraine Episodes

[0328] The purpose of the experiments described in this Example was todetermine the efficacy of dorsonasal administration of ropivacaine forinhibition of acute migraine episodes. Ropivacaine was dorsonasallyadministered to individual patients experiencing head pain, othersymptoms, or both, believed to be associated with an acute migraineepisode. Patients assessed head pain prior to and after ropivacaineadministration.

[0329] Dorsonasally administered ropivacaine rapidly inhibited ofmigraine in 92% of the ambulatory patients, as evidenced by an average90% reduction in perceived pain within one hour, usually within 15minutes or less. Symptoms of nausea and photophobia associated withacute migraine episodes in patients were similarly inhibited. Rebound ofmigraine occurred in only 5.4% of patients within twenty-four hours oftreatment. These results demonstrate that dorsonasal administration ofropivacaine is an efficacious method of inhibiting an acute migraineepisode.

[0330] The materials and methods used in the procedures performed inthis Example are now described.

[0331] Ropivacaine Composition

[0332] Ropivacaine-HCl (NAROPIN™, Astra USA, Westborough, Mass.) wasused as the commercially-available 0.75% (w/v) solution, and wasobtained in 30 milliliter, sterile injectable vials.

[0333] Methods of Ropivacaine Administration

[0334] Three methods were used to achieve dorsonasal delivery ofropivacaine to individual patients. Ropivacaine was administered to afirst group of patients by an intranasal drip method. Ropivacaine wasadministered to a second group using cotton swabs, the absorbentportions of which were saturated with the ropivacaine solution.Ropivacaine was administered to patients in a third group by sprayingthe ropivacaine solution into each nostril, using either a squeeze-typespray bottle or a metered-dose spray bottle.

[0335] The intranasal drip method used to administer ropivacaine to thefirst group of patients was a based on the method described by Barre(1982, Headache 22:69-73), except that the ropivacaine solution was usedin place of the solution used by Barre. Approximately 0.75 milliliter toapproximately 1.0 milliliter of the ropivacaine solution wasadministered by way of each of the nostrils of each patient.

[0336] The cotton swab method used to administer ropivacaine to thesecond group of patients comprised gently inserting cotton swabs,sequentially and bilaterally, into the nostrils of patients and urgingthe swabs dorsally until their absorbent portions contacted portions ofnasal epithelium located dorsal to the middle conchae. Each swab wasleft in place for approximately one minute, and was then withdrawn.Approximately 0.5 milliliter of the ropivacaine solution was deliveredto each nostril using this method.

[0337] Patients in a third group were administered ropivacaine byspraying less than about 0.5 milliliter of the ropivacaine solution intoeach of the patient's nostrils using either a sterile squeeze bottle ora sterile metered-dose spray bottle of known design. The design andoperation of each of these spray bottles are well known in the art.

[0338] Prior to administration of ropivacaine, each patient was placedin a supine position with the patient's head hyperextended approximately45 degrees and rotated approximately 30 degrees to the right side. Inthis position, an imaginary line extending from the region of the nasalepithelium overlying the SPG of the patient through the patient's leftnostril was approximately vertical. Ropivacaine was then administered tothe left nostril of the patient as described for each of the threegroups of patients. Ropivacaine was administered to each patient's rightnostril after rotating the patient's head approximately 30 degrees tothe left. Ropivacaine was administered to both nostrils of each patientto prevent cases of unilateral migraine from developing intocontralateral migraine.

[0339] Assessing Ropivacaine-Induced Pain Relief

[0340] Prior to ropivacaine administration, each patient rated perceivedheadache pain according to a standard pain scale of the type used in theart. Patients were asked to rank the severity of pain which they wereexperiencing on a scale from 0 (no pain) to 10 (worst pain imaginable).This ten-point pain rating scale is analogous to, but has moregradations than, the four-point rating system used by the InternationalHeadache Society (IHS; Headache Classification Committee of theInternational Headache Society, 1988, Cephalalgia 8(Suppl. 7):19-28).Ropivacaine was administered to one nostril of each patient, and then tothe other. The time required to administer ropivacaine to both nostrilsof each patient was approximately three minutes. Five minutes after thecompletion of administration of ropivacaine to the patient's firstnostril, each patient again rated perceived headache pain. If no painrelief was evident, dosing was repeated, and the rating procedure wasrepeated. Pain ratings were obtained for each patient until peak effectappeared to be achieved, for up to ninety minutes, acutely. Follow-up ofeach patient's condition was attempted by direct contact or by telephonecontact between six and eight hours post-treatment, between twenty-fourand forty-eight hours post-treatment, and up to one week post-treatment.

[0341] The results obtained from the procedures performed in thisExample are now described.

[0342] The population of patients treated in the procedures performed inthis Example comprised forty-two adults, each of whom sought migrainerelief. The results of treatment of each of these patients with eitherropivacaine or (for three patients) lidocaine are presented in Table 1.The five patients who were either treated with lidocaine or did notclearly meet the IHS criteria for migraine were not included in theanalysis presented herein of the efficacy of dorsonasal ropivacainetreatment of migraine. The demographic and pretreatment characteristicsof the patients who met IHS migraine criteria and who were treated withropivacaine are presented in Table 2. TABLE 1 Summary of Patient Data.Patient Medical Headache Associated Identifier History¹ History²Symptoms³ Treatment⁴ Results⁵ P#1 Posterior Migraine Mild Nausea R 0.75%Initial pain: 8 Photophobia 2 Sprays Pain 10 min post-treatment: 0 Norebound up to 24 hours P#2 Head Trauma Constant R 0.75% No Relief⁶Resulting From Headache for circa 2 cc Drops Auto Accident 28 years P#3Meningitis circa Monthly Head- R 0.75% Transient Improvement⁶ 26 yearsaches of circa 3 2 cc Drops pretreatment day duration P#4 Post PartumMigraine R 0.75% Initial pain: 9 Headaches 2 cc Drops Pain 3 minpost-treatment: 0 No rebound up to 24 hours P#5 Posterior and Nausea R0.75% Initial pain: 9 Lateral Migraine Photophobia 2 cc Drops Pain 15min post-treatment: 0 No rebound up to 24 hours P#6 Post Partum Temporaland R 0.75% Initial pain: 8 Headache Frontal Headache Sat'd Cotton Pain5 min post-treatment: 0 Swab No rebound up to 24 hours P#7 Temporal andVisual R 0.75% Initial pain: 10 Frontal Headache Changes Sat'd CottonPain 2 min post-treatment: 0 of 2-3 Day Swab No rebound up to 24 hoursor up Duration to 48 hours P#8 Patient's First Loss of Vision R 0.75%Initial pain: 10 Vascular Bed-ridden Sat'd Cotton Pain 10 minpost-treatment: 0 Headache Episode Swab Pain 24 hours post-treatment: 1(CT scan ruled out (this pain was relieved by subarachnoid administeringa 325 milligram hemorrhage) Tylenol ™ (McNeil-PPC, Inc., FortWashington, PA) tablet) No rebound up to two weeks P#9 Migraine R 0.75%Initial pain: 8.5 Sat'd Cotton Pain 5 min post-treatment: 1 Swab Norebound up to 3 days P#10 Migraine Nausea R 0.75% Initial pain: 9Photophobia Sat'd Cotton Pain 3 min post-treatment: 0 Swab No rebound upto one week P#11 Occipital Must lie down R 0.75% Initial pain: 9Headache few 2 cc Drops Pain 15 min post-treatment: 5 times per yearPain 60 min post-treatment: 0 No rebound up to one week P#12 Migraine L2.0% Initial pain: 7 1 cc Drops Pain 5 min post-treatment: 2 Pain 45 minpost-treatment:6^(B) P#13 Marfan's Migraine Mild Nausea R 0.75% Initialpain: 6 Syndrome 2 Sprays Pain 30 min post-treatment: 0⁶ No rebound upto 24 hours P#14 Migraine Nausea R 0.75% Initial pain: 8 (Worst duringPhotophobia Sat'd Cotton Pain 3 min post-treatment: 0 menses) Visualchanges Swab Pain 5 min post-treatment: 2 Retreated Pain 18 hrspost-treatment: 8 with (After 18 hrs, treated w/spray) 2 Sprays Painfollowing spray: 0⁶ No rebound up to 48 hours P#15 Viral Sinus HeadacheVertigo L 2.0% Initial pain: 6 Gastrointestinal developed 1 cc DropsPain 15 min post-treatment: 0 Disturbance after sneeze Pain 30 minpost-treatment: 6 P#16 Post Partum Post Dural L 2.0% Initial pain: 8Headache Puncture 1 cc Drops Pain 15 min post-treatment: 4⁶ HeadacheP#17 Migraine Nausea R 0.75% Initial pain: 8 Photophobia 2 Sprays Pain15 min post-treatment: 2 Pain 20 min post-treatment: 0⁶ No rebound up to48 hours P#18 Migraine Visual changes R 0.75% Initial pain: 9 Sat'dCotton Pain 3 min post-treatment: 0 Swab P#19 Lumbar Disc Migraine R0.75% Initial pain: 9 Surgery Sat'd Cotton Pain 1 min post-treatment: 0Swab No rebound up to 48 hours P#20 Congenital Migraine Nausea R 0.75%Initial pain: 8 Megacolon Vomiting Sat'd Cotton Pain 3 minpost-treatment: 0 Swab No rebound up to one week P#21 Migraine Nausea R0.75% Initial pain: 10 Sat'd Cotton Pain 3 min post-treatment: 1 SwabPain 5 min post-treatment: 0 No rebound up to one week P#22 Cervical andR 0.75% Initial pain: 8 Occipital Sat'd Cotton Pain 10 minpost-treatment: 0 Headache Swab No rebound up to 24 hours P#23 CervicalSpine Cervical and Nausea R 0.75% Initial pain: 9 Pain Occipital Sat'dCotton Pain 5 min post-treatment: 1 Headache Swab No rebound up to 24hours P#24 Migraine R 0.75% Initial pain: 9 Sat'd Cotton Pain 3 minpost-treatment: 0 Swab P#25 Recurrent Parietal Nausea R 0.75% Initialpain: 10 and Occipital Visual changes Sat'd Cotton Pain 3 minpost-treatment: 0 Headaches, Swab No rebound up to one week BilateralTemporal Headaches P#26 Migraine Nausea R 0.75% Initial pain: 10Photophobia Sat'd Cotton Pain 5 min post-treatment: 0 Swab No rebound upto 24 hours P#27 Recurrent Frontal, Nausea R 0.75% Initial pain: 10Parietal, Photophobia Sat'd Cotton Pain 8 min post-treatment: 0Temporal, and Swab No rebound up to 48 hours Occipital Headaches P#28Migraine Nausea R 0.75% Initial pain: 9 Visual changes Sat'd Cotton Pain5 min post-treatment: 0 Swab No rebound up to 48 hours P#29 MigraineNausea R 0.75% Initial pain: 10 Photophobia Sat'd Cotton Pain 5 minpost-treatment: 0 Swab No rebound up to 24 hours P#30 Temporal MigraineNausea R 0.75% Initial pain: 9 Arteritis, Steroid Sat'd Cotton Pain 10min post-treatment: 1 Use Swab No rebound up to 18 hours P#31 Migraine R0.75% Initial pain: 9 Sat′d Cotton Pain 2 min post-treatment: 1 Swab Norebound up to 24 hours P#32 Chemotherapy Migraine Nausea R 0.75% Initialpain: 10 Sat′d Cotton Pain 15 min post-treatment: 0 Swab P#33Hypertension, Migraine Nausea, R 0.75% Initial pain: 9 Controlled DietPhotophobia, 2 Metered Pain 5 min post-treatment: 5 Visual changesSprays Pain 30 min post-treatment: 3 Pain 90 min post-treatment: 0(Patient presented one week later) Migraine 2 Metered Initial pain: 10Sprays Pain 15 min post-treatment: 5 Pain 30 min post-treatment: 4 Pain90 min post-treatment: 0 No rebound up to one week P#34 Major MigraineNausea, R 0.75% Initial pain: 7 Depression, Photophobia 2 Metered Pain20 min post-treatment: 3 Chronic Sprays (Then repeated treatment usingHepatitis C two metered sprays) 2 Metered Pain 5 min post-treatment: 0Sprays (Patient presented seven hours later) 2 Metered Initial pain: 2Sprays Pain 10 min post-treatment: 0 No rebound up to 24 hours P#35 HeadTrauma Migraine Nausea, R 0.75% Initial pain: 8 Visual changes 2 MeteredPain 30 min post-treatment: 6 Sprays Pain 60 min post-treatment: 2 P#36Complaints of Migraine Nausea, R 0.75% Initial pain: 9 “Stuffy Nose”Photophobia, 2 Metered Pain 5 min post-treatment: 7 Visual changesSprays Pain 30 min post-treatment: 5 P#37 Atypical Right Nausea, R 0.75%Initial pain: 7 Side Headache Photophobia, 2 Metered Pain 30 minpost-treatment: 3 Behind Eye Intense Eye Sprays Pain 45 minpost-treatment: 0 Pain & (Patient presented three days Pressure later) 2Metered Initial pain: 2 Sprays Pain 10 min post-treatment: 0 No reboundup to 48 hours P#38 Head Trauma Migraine R 0.75% Initial pain: 3 2Metered Pain 30 min post-treatment: 0 Sprays P#39 Migraine Nausea R0.75% Initial pain: 9 2 Sprays Pain 2 min post-treatment: 0 No reboundup to 48 hours P#40 Migraine Mild Nausea R 0.75% Initial pain: 10 Sat'dCotton Patient exhibited apparent Swab allergic reaction between 5 and15 minutes post-treatment Pain 20 min post-treatment: 3 Pain 30 minpost-treatment: 5 Level 5 pain endured 8 hours P#41 Head TraumaRecurrent Nausea, R 0.75% Initial pain: 8 Headaches Photophobia, Sat'dCotton Pain 20 min post-treatment: 0 Perceived Swab No rebound up to 48hours ‘Whistling Sounds’ P#42 Migraine Perceived R 0.75% Initial pain: 9‘Flashing Sat'd Cotton Pain 2 min post-treatment: 0 Lights’ Swab Norebound up to one week #the patient using a sterile squeeze bottlecontaining the solution; “# cc Drops” refers to delivery of #milliliters of the indicated solution via the modified nasal drip methoddescribed herein; “Sat'd Cotton Swab” refers to delivery of theindicated solution using a standard cotton swab saturated with theindicated solution as described herein; “2 Metered Sprays #” refers todelivery of less than about 0.5 milliliter of the indicated solutiondelivered by a combination of two sprays into each nostril of thepatient using a sterile metered-dose spray bottle containing thesolution.

[0343] TABLE 2 Demographic and Pretreatment Characteristics of Patients.Characteristic Value Mean Age (Standard Error; Range) 45.1 years (±2.1years; 22-67) GenderMale   17 (45.9%) Female   20 (54.1%) Duration ofCurrent Headache, hours 23.2 (±4.1) (Standard Error) Mean Pain Level on10-Point Scale 8.64 (±0.223; 8.18-9.09) (Standard Error; 95% conf.interval) Patients Experiencing Nausea   23 (62.1%) PatientsExperiencing Photophobia   14 (37.8%)

[0344] Thirty-four of the thirty-seven (92%) migraine patients treatedwith ropivacaine experienced significant (i.e., certainly greater than50%) reduction of migraine severity. Complete relief followedropivacaine administration in 72% of the patients. Photophobia, nausea,and pain were simultaneously eliminated in migraine patients whoexperienced each of these symptoms. Rebound was evident in only two ofthe responding patients, meaning that the rebound rate was only 5.4%.Adverse effects of ropivacaine administration were minimal: one patientexperienced an allergic response to ropivacaine administration, whichresponse consisted of short-lived tachycardia, dizziness, and wheezing,all of which endured for about twenty minutes before subsiding. Eventhis patient who experienced an allergic response experienced ameasurable reduction of migraine pain within twenty-five minutespost-treatment.

[0345] Pain Relief Effected by Cotton-Swab-Application of Ropivacaine

[0346] Among the twenty-four patients to whom ropivacaine wasdorsonasally administered using a cotton swab, the mean pain severityrating prior to administration of ropivacaine was 9.06±0.16 points outof a possible 10 points (mean±standard error). The meanpost-administration pain severity rating at the time of peak effect was0.33±0.14 points out of a possible 10 points. Thus, dorsonasaladministration of ropivacaine using a cotton swab resulted in a meanpeak headache severity rating reduction of 8.73±0.249 points. The meantime that elapsed between the time of treatment and the perception bythe patient of the peak effect was 7.41±1.47 minutes. Every patient inthis group responded to treatment, 95% of the patients achieving a painseverity rating of zero or one, and 72% of patients achieving a painseverity rating of zero. One patient in this group experienced reboundof headache pain eighteen hours post-treatment. Thus, dorsonasaladministration of ropivacaine using a cotton swab causes significantpain reduction in 100% of migraine patients, with rebound occurring inonly 4% of patients.

[0347] Pain Relief Effected by Nasal-Drip-Application of Ropivacaine

[0348] Dorsonasal administration of ropivacaine effected by delivery ofnasal drops resulted in a mean peak headache severity rating reductionof 9.00 points out of a possible 10 points in the three patients sotreated. The mean time that elapsed between the time of treatment andthe perception by the patient of the peak effect was 26.00±17.37minutes. None of the three patients experienced migraine rebound.

[0349] Pain Relief Effected by Nasal-Spray-Application of Ropivacaine

[0350] Dorsonasal administration of ropivacaine effected by deliveryusing the nasal spray method resulted in a mean peak headache severityrating reduction of 6.22±0.66 points out of a possible 10 points in theten patients so treated. The mean time that elapsed between the time oftreatment and the perception by the patient of the peak effect was33.9±8.48 minutes. Of the ten migraine patients treated by intranasalspray, all experienced significant reduction in headache pain severity.The majority of these patients experienced complete headache pain reliefand did not experience rebound. The remainder experienced a meanheadache pain severity rating reduction of 87.5±6.49%. One of the tenpatients to whom ropivacaine was administered using a spray bottleexperienced a separate episode of migraine one week later.

[0351] Comparison of Administration of Ropivacaine by Cotton Swab, byNasal Drops, and by Nasal Spray

[0352] The results obtained in patients who were administeredropivacaine by the three methods described herein are summarized inTables 3 and 4. TABLE 3 Effect of the Route of RopivacaineAdministration on Severity of Migraine Pain. Pain Ratings and PainRelief are measured using a 10-point pain scale, as described herein.Method of Pain Rating Prior Pain Rating After Delivery to AdministrationAdministration Pain Relief Cotton Swab 9.06 0.33 8.73 Nasal Drops 9.000.00 9.00 Nasal Spray 7.22 1.00 6.22

[0353] TABLE 4 Effect of the Route of Ropivacaine Administration onSeverity of Migraine Pain. Rate of Pain Mean Relief Number Reduction inMean Time (IHS of Pain Rating Until Maximal points per Method ofDelivery Patients (IHS points) Effect minute) Cotton Swab 24 8.64 7.412.32 (Standard Error) (±0.25) (±1.46) 95% confid. interval 8.12-9.164.37-10.4 Nasal Drops 3 9.00 26.0 1.25 (Standard Error) (0) (±12.3) 95%confid. interval 5.89-10.6  0-100 Nasal Spray 10 6.22 33.9 0.287(Standard Error) (±0.66) (±8.48) 95% confid. interval 4.69-7.7514.31-53.46

[0354] Comparison of the Therapeutic Effect of Dorsonasally-AdministeredRopivacaine and the Therapeutic Effect of Intranasally-AdministeredLidocaine

[0355] The anesthetic effect of 0.75% (w/v) ropivacaine-HCl isapproximately equivalent to that of 3% (w/v) lidocaine. Intranasal sprayadministration of 1-2 milliliters of a 4% (w/v) lidocaine solution was55% effective to reduce pain associated with migraine (Maizels et al.,1996, J. Amer. Med. Assoc. 276:319-321). By comparison, as describedherein, dorsonasal spray administration of a 0.75% (w/v) ropivacainesolution was 100% effective to reduce pain associated with migraine.Furthermore, when dorsonasal administration of the ropivacaine solutionwas effected by topical application using a cotton swab saturated withthe solution, reduction of migraine pain was achieved in 100% ofpatients. Preliminary data indicate that bupivacaine exhibits efficacysimilar to that of ropivacaine for the relief of headache painassociated with migraine.

[0356] A comparison of ropivacaine and lidocaine on the basis ofmigraine pain relief per unit weight is provided in Table 5. Thiscomparison indicates that dorsonasally spray-administered ropivacaine is2.4 times as potent as intranasally spray-administered lidocaine, andthat dorsonasally swab-administered ropivacaine is more than 15 times aspotent as intranasally spray-administered lidocaine. Furthermore, asindicated in Table 5, the rate of migraine rebound is much lowerfollowing dorsonasal administration of ropivacaine, whether administeredby nasal spray or by cotton swab, than it is following intranasaladministration of lidocaine. Thus, the data presented herein indicatethat ropivacaine is a much more efficacious agent for migraine painrelief than is lidocaine and that treatment of migraine by dorsonasalropivacaine administration has a significantly lower rebound rate thantreatment by intranasal administration of lidocaine. TABLE 5 Comparisonof the efficacy of migraine treatment by dorsonasal ropivacaineadministration and the efficacy by intranasal lidocaine administration.“Rate” indicates the rate of migraine pain reduction per minute per gramof drug administered to the patient. Pain was rated using a 10-pointpain scale, as described herein. Route of Rate of Relative Rebound DrugAdministration Pain Relief Efficacy¹ Rate Lidocaine Intranasal Spray10.0 1.00 42% Ropivacaine Dorsonasal Spray 24.5 2.45 10% RopivacaineDorsonasal Swab 155 15.5 4%

[0357] Comparison of the Therapeutic Effect of Ropivacaine and theTherapeutic Effects of Other Anti-Migraine Pharmaceutically activeagents

[0358] In FIG. 3, the data obtained from the procedures performed inthis Example are presented and compared with recently reported dataobtained for administration of lidocaine to migraine patients (Maizelset al., 1996, J. Amer. Med. Assoc. 276:319-321) or administration ofsumatriptan to migraine patients (The Subcutaneous SumatriptanInternational Study Group, 1991, New Eng. J. Med. 325:316-321).Administration of ropivacaine resulted in an earlier onset of relief anda higher response rate than did administration of sumatriptan. Althoughthe time of onset of relief using ropivacaine was roughly equal to thetime of onset of relief using lidocaine, administration of ropivacainetreatment resulted in a nearly two-fold greater response rate than didadministration of lidocaine. The response rate obtained byadministration of ropivacaine to migraine patients was greater than theresponse rate obtained by administration of rizatriptan to suchpatients. In addition, the rebound rate following ropivacaineadministration was lower than the rebound rate following rizatriptanadministration (Kramer et al., 1997, Headache 36:268-269). The rapid andnon-relapsing effects attributable to dorsonasal administration ofropivacaine are not observed following administration of lidocaine or aserotonin receptor agonist administered by the same route (Mills et al.,1997, Ann. Pharmacother. 31:914-915; Moore et al., 1997, Cephalalgia17:541-550; Kramer et al., 1997, Headache 36:268-269).

[0359] While not wishing to be bound by any particular theory ofoperation, it is believed that dorsonasally administered ropivacaineinhibited migraine by anesthetizing a DnNS such as the SPG. Ropivacaineis ideally suited for anesthesia of a DnNS in general, and for migrainerelief in particular. Ropivacaine exhibits intermediate lipid solubilityand an intermediate half life in vivo, properties that limit possibletoxicity. Direct application of ropivacaine to the region of the nasalepithelium overlying the SPG reduces the likelihood of systemicdistribution of the compound, thereby limiting the likelihood ofnumerous side effects. Furthermore, direct application of ropivacaine tothe region of the nasal epithelium overlying the SPG reduces the amountof ropivacaine which must be administered in order to provide aneffective concentration at the SPG for relief of an acute migraineepisode. Ropivacaine and other local anesthetics related to aminoacyllocal anesthetics are known to selectively affect sensory neurons,relative to motor neurons, representing another advantage of usingropivacaine in the method of the invention. It is believed that directadministration of ropivacaine to the region of the nasal epitheliumoverlying the SPG, or to the region of the nasal epithelium near thatregion, arrests the cascade of neurotransmitter and neuropeptide releaseand stimulation that lead to neurogenic inflammation observed in thecourse of an acute migraine episode.

[0360] The ropivacaine molecule has the following structure (V), whereinthe carbon atom indicated by the asterisk is a chiral center:

[0361] Cardiotoxicity is a side effect of administration of theR(dextro) enantiomer of ropivacaine, but this side effect is notexhibited by the S(levo) enantiomer (dejong, 1995, Reg. Anesth.20:474-481). For this reason, ropivacaine is prepared as a sterilesolution containing only the S(levo) enantiomer. The bupivacainemolecule also comprises a chiral center, but currently commerciallyavailable bupivacaine preparations include both the S and the Renantiomers.

[0362] Many of the patients described in this Example were observed forup to seven days, and 95% of those patients experienced no reboundduring this period. This result contrasts with the results obtainedfollowing intranasal lidocaine administration. Of the 55% of patientswho exhibited relief following intranasal lidocaine administration, atleast 42% experienced rebound, usually within one hour post-treatment(Maizels et al., 1996, J. Amer. Med. Assoc. 276:319-321). Similarly,administration of either sumatriptan or rizatriptan resulted ininhibition of pain in 40-50% of patients within two hours posttreatment, and patients who were administered either of these compoundsfrequently experienced rebound (The Subcutaneous SumatriptanInternational Study Group, 1991, New Eng. J. Med. 325:316-321; Kramer etal., 1997, Headache 36:268-269).

EXAMPLE 2

[0363] Dorsonasal Administration of Bupivacaine for Inhibition of AcuteMigraine Episodes

[0364] The purpose of the experiments described in this Example was todetermine the efficacy of dorsonasal administration of bupivacaine forinhibition of acute migraine episodes. Bupivacaine was dorsonasallyadministered to individual patients experiencing head pain, othersymptoms, or both, believed to be associated with an acute migraineepisode. Patients assessed head pain prior to and after bupivacaineadministration.

[0365] Dorsonasally administered bupivacaine provided rapid arrest ofmigraine in all seven patients to whom it was administered within 10minutes or less. Symptoms such as nausea, visual changes, andphotophobia associated with acute migraine episodes in the patients weresimilarly reduced. Six of the seven patients treated using bupivacaineexperienced no rebound of their migraine within twenty-four hours oftreatment. The other patient experienced a recurrence of head pain fourhours following a first administration of bupivacaine and anotherepisode of head pain eight hours following a second administration ofbupivacaine. These results demonstrate that dorsonasal administration ofbupivacaine is an efficacious method of inhibiting an acute migraineepisode.

[0366] The materials and methods used in the procedures performed inthis Example were substantially the same as the materials and methodsdescribed in Example 1, with the exception that the composition whichwas administered to the patients described in this example comprised a0.75% (w/v) solution of bupivacaine.

[0367] The results of treatment of each of the seven patients describedin this Example with bupivacaine are presented in Table 6. Theorganization of and the abbreviations used in Table 6 are analogous tothose used in Table 1, with the exception that “B” in the treatmentcolumn refers to bupivacaine. These results indicate that dorsonasaladministration of bupivacaine is effective to inhibit acute migraineepisodes. TABLE 6 Summary of Patient Data. Patient Medical HeadacheAssociated Identifier History History Symptoms Treatment Results P2#1Migraine Nausea B 0.75% Initial pain: 5 2 Sprays Pain 10 minpost-treatment: 0 No rebound up to 24 hours P2#2 Migraine Nausea B 0.75%Initial pain: 7 Photophobia Sat'd Cotton Pain 5 min post-treatment: 0Swab No rebound up to 24 hours P2#3 Migraine Visual Changes and nauseaas B 0.75% Initial pain: 10 aura. Followed by head pressure 2 cc DropsPain 5 min post-treatment: 1-2 and severe head pain at right Headpressure persisted occipital to front areas No rebound up to 24 hoursP2#4 Sinus Migraine B 0.75% Initial pain: 8 Surgery Triggered 2 SpraysPain 5 min post-treatment: 0 by Recurrence 4 hours Chocolatepost-treatmt. Pain 5 min Ingestion post-2nd-treatment: 0 Recurrence 8hours post-treatmt. P2#5 Mixed Nausea B 0.75% Initial pain: 8 HeadachePhotophobia 2 Sprays Pain 10 min post-treatment: 0 No rebound up to 24hours P2#6 Migraine B 0.75% Initial pain: 8 2 Sprays Pain 3 minpost-treatment: 0 No rebound up to 24 hours P2#7 Migraine Visual ChangesB 0.75% Initial pain: 10 2 cc Drops Pain 10 min post-treatment: 0 Norebound up to 24 hours

EXAMPLE 3

[0368] Inhibiting a Recurring Cerebral Neurovascular Disorder byDorsonasally Administering a Long-acting Local Anesthetic Decreases theFrequency and Severity of Subsequent Episodes

[0369] The following studies relate to the methods of decreasing thefrequency and severity of CNvD episodes described herein, and involvedthree patients.

[0370] A 25-year-old female patient, herein designated “patient 3-1” wasafflicted with recurring severe migraine, wherein acute migraineepisodes were associated with nausea and visual changes. Patient 3-1generally rated the severity of head pain associated with acute migraineepisodes in the range from five to eight using the pain scale describedherein. Patient 3-1 experienced, on average, about one acute migraineepisode per week prior to beginning dorsonasal ropivacaine therapy. Inaddition, patient 3-1 also usually experienced about one severe acutemigraine episode per month, associated with menses, wherein the severityof head pain was from eight to ten using the pain scale describedherein. Patient 3-1 did not respond satisfactorily to administration ofbeta blockers and sumatriptan.

[0371] Ropivacaine was dorsonasally administered to patient 3-1 usingthe cotton swab technique described herein. The patient has consistentlyexperienced relief from all of the symptoms of her CNvD episodes within3 to 5 minutes following administration of ropivacaine, regardless ofwhether the episodes are associated with menses.

[0372] Patient 3-1 has continued treatment according to this method forabout six months. After beginning the ropivacaine treatment, the patientdiscontinued use of sumatriptan and propanolol. Discontinuing thesemedications did not result in a loss of efficacy attributable toropivacaine administration. Starting about three or four monthsfollowing initiation of ropivacaine administration, the patient noticeda decrease in the initial severity of acute migraine episodes notassociated with menses. At about the same time, the patient furthernoticed a decrease in the frequency with which acute migraine episodesnot associated with menses occurred. No decrease in either the initialseverity or the frequency of acute migraine episodes associated withmenses has been reported by the patient. Patient 3-1 continues toexperience relief from the head pain and other symptoms of acutemigraine episodes, including those associated with menses, uponadministration of ropivacaine.

[0373] A 45-year-old male, herein designated, “patient 3-2,” wasafflicted with recurring migraines. The acute migraine episodes beganwhen he was a teenager, and have significantly worsened over the past 15years. Head pain associated with the patient's acute migraine episodesis typically preceded by visual changes which he describes as acurtain-like wave of scotomata moving from left to right until he isunable to see. The patient then becomes disoriented with respect to timeand place and must sit or lay down. Following these prodromal symptoms,a severe headache, rated 10 on the pain scale described herein, beginsand typically endures for 45 to 60 minutes. The patient remainscompletely debilitated for the duration of the headache, unable to moveabout or walk. As the headache subsides, the patient's vision returns,and the patient is left feeling exhausted, as if he had not slept thenight before.

[0374] Following dorsonasal administration of ropivacaine, delivered bythe nasal spray method described herein, patient 3-2 noticed an abrupthalt to the progression of visual changes and steady resolution of hisvisual deficit. The headache rapidly decreased in intensity, decreasingfrom a pain intensity of 10, using the pain scale described herein, toan intensity of 2-3 within one to two minutes. The headache wascompletely resolved by fifteen minutes following ropivacaineadministration. This patient also noted that he did not feel exhaustedfollowing the treated acute migraine episode. After four to six monthsof dorsonasal ropivacaine therapy, the patient noted that his headachesoccurred less frequently, at a rate of approximately one headache everytwo months or longer. Furthermore, the severity of the headaches thatpatient 3-2 experienced was significantly reduced following this courseof therapy. Prior to the course of dorsonasal ropivacaine therapy, thepatient's headaches ordinarily had a pain intensity of about 10; afterfour to six months of this therapy, the initial headache pain (i.e.,even prior to ropivacaine administration) was not greater than about 2.The patient reports significant lifestyle improvement, and is not awareof any other changes, for example changes in diet, sleep, exercise,environment, or medication, that could account for this improvement.

[0375] A 40-year-old female, herein designated, “patient 3-3,”experienced about 3 to 5 recurring migraine episodes per week prior tobeginning dorsonasal ropivacaine therapy. The initial severity of theseheadaches was reported to be 10, using the pain scale described herein.When ropivacaine was administered, using the saturated swab methoddescribed herein, to patient 3-3 during a headache episode, the patientreported a decrease in head pain from a rating of 10 to a rating of 0 or1 within 10 minutes following ropivacaine administration. Furthermore,after three months of dorsonasal ropivacaine treatment, patient 3-3reported that the frequency of her headache episodes had decreased toabout 1 to 2 times weekly and that the initial severity of her headacheswas in the range from about 7 to about 8, rather than 10.

[0376] The data described in this Example indicate that dorsonasaladministration of ropivacaine to a patient afflicted with a recurringCNvD both inhibits a single episode of the CNvD and decreases thefrequency and initial severity of the episodes associated with therecurring CNvD. Thus, the compositions, kits, and methods of theinvention are useful for decreasing the frequency with which a patientafflicted with a recurring CNvD experiences a CNvD episode and forotherwise inhibiting the CNvD.

EXAMPLE 4

[0377] Inhibition of Tinnitus by Dorsonasal Administration ofRopivacaine

[0378] The data presented in this example demonstrate that symptoms oftinnitus may be inhibited by dorsonasal administration of a localanesthetic. Ropivacaine was dorsonasally administered to each of threepatients using the nasal spray method or the nasal drops methoddescribed herein. All three patients experienced inhibition of tinnitus.

[0379] The first patient, herein designated, “patient 4-1,” was ahealthy male patient in his thirties who was afflicted with occasionalmigraines complicated by bilateral tinnitus about once every two tothree months. Dorsonasal spray administration of ropivacaine to patient4-1 relieved the head pain and tinnitus symptoms experienced by thispatient within about five minutes following administration.

[0380] The second patient, herein designated, “patient 4-2,” was a malein his forties who was afflicted with chronic head, neck, back, andshoulder pain resulting from trauma sustained during multiple motorvehicle accidents. Patient 4-2 was afflicted with constant head pain forwhich he used large quantities of intranasally-administered butorphanol.It was believed that the patient's headaches did not have aneurovascular etiology. Patient 4-2 is also afflicted with continuousbilateral tinnitus. Following dorsonasal spray administration ofropivacaine to patient 4-2, the patient reported a decrease in head painof about 2 points, using the pain scale described herein, andfurthermore experienced complete relief from symptoms of tinnitus for aperiod of 30 to 45 minutes. Interestingly, this patient noted a fasteronset and a far more powerful effect on his chronic non-headache pain ofintranasally administered butorphanol following intranasaladministration of ropivacaine.

[0381] The third patient, herein designated, “patient 4-3,” was ahealthy male in his sixties who was afflicted with bilateral tinnitusfor over 30 years. Following dorsonasal administration of 1 milliliterof 0.75% (w/v) ropivacaine into each nostril by the nasal drop methoddescribed herein, patient 4-3 experienced complete relief from tinnitussymptoms in his left ear and a 50-75% reduction in tinnitus symptoms inhis right ear. This patient's relief from and reduction of symptomspersisted for about 30 to 45 minutes, after which period the tinnitussymptoms returned.

[0382] The results of the experiments described in this Example indicatethat dorsonasal administration of a local anesthetic inhibits tinnitus.Even though the relief of tinnitus in these three patients wasrelatively short-lived (relative to migraine relief, as describedherein), it must be borne in mind that no effective treatment exists fortinnitus. Thus, the treatment method described herein for tinnitus canbe used to provide at least temporary relief to patients who have noeffective long-term treatment options. Furthermore, the resultspresented in this Example suggest that a sustained release preparationof a local anesthetic or a local anesthetic causing a longer duration ofanesthesia than ropivacaine may provide a longer period of inhibition oftinnitus than the ropivacaine preparation used in this method.

EXAMPLE 5

[0383] Dorsonasal Administration of Bupivacaine for Treatment ofMuscular Headache Episodes

[0384] The purpose of the experiments described in this Example was todetermine the efficacy of dorsonasal administration of bupivacaine forinhibition of muscular headaches. Bupivacaine was dorsonasallyadministered to four individual patients experiencing head pain andother symptoms associated with a severe muscular headache episode. Allof the patients had areas of sustained craniocervical muscle contractionand tenderness which was absent in all patients following headacheresolution. Patients assessed head pain prior to and after bupivacaineadministration. The four patients and their responses were as follows.

[0385] Patient 1

[0386] This patient was a 68-year-old female who experienced classictension headache symptoms under stress. The patient normally experiencedrelief of tension headache symptoms following administration ofibuprofen. The patient was administered 0.75% bupivacaine during atension headache episode, and thereafter experienced relief of herheadache symptoms. The patient's pain intensity, as assessed using thepain scale described herein, decreased from about 8 to 0 within about 15minutes after bupivacaine administration.

[0387] Patient 2

[0388] This patient was a 38-year-old male who experienced typicalmuscle contraction headache symptoms. The patient normally experiencedrelief of headache symptoms following administration of acetaminophen.The patient was administered 0.75% bupivacaine during a musclecontraction headache episode, and thereafter experienced relief of hisheadache symptoms within seven minutes following bupivacaineadministration. The patient's pain intensity, as assessed using the painscale described herein, decreased from about 7 to 0 within about 7minutes after bupivacaine administration.

[0389] Patient 3

[0390] This patient was a 25-year-old male who experienced cervical neckpain symptoms associated with tension headache. The patient experiencedmoderate relief of headache symptoms following administration ofnon-steroidal anti-inflammatory drugs, including ibuprofen. The patientwas administered 0.75% bupivacaine during a tension headache episode,and thereafter experienced relief of his headache symptoms. Thepatient's pain intensity, as assessed using the pain scale describedherein, decreased from about 5 to about 1 within about 5 minutes afterbupivacaine administration.

[0391] Patient 4

[0392] This patient was a 44-year-old female who experienced tensionheadaches. The patient was administered 0.75% bupivacaine during atension headache episode, and thereafter experienced relief of neck painand bi-temporal tension headache pain symptoms. The patient's painintensity, as assessed using the pain scale described herein, decreasedfrom about 7 to about 1 within about 5 minutes after bupivacaineadministration. Prior to bupivacaine administration, the patientexperienced mild residual pain in response to deep palpation of affectedneck and temple muscles. This pain was perceived to be markedlydecreased following treatment, and muscle knots were no longer perceived5 minutes after treatment.

[0393] It is recognized that the muscular headache inhibition describedin this Example may have been secondary to neurovascular effects of adorsonasally administered local anesthetic or to effects on one or bothof intracranial or extracranial neural or vascular structures, asdescribed herein.

EXAMPLE 6

[0394] Dorsonasal Administration of a Eutectic Mixture of LocalAnesthetics

[0395] An amount (0.5-1.0 milliliters) of a commercially availableeutectic mixture of local anesthetics (prilocaine/lidocaine, 2.5% (w/v)each; EMLA™, Astra USA, Westborough, Mass.) was dorsonasallyadministered to each of six healthy adults using a syringe having aflexible applicator attached thereto. None of the six adults notedoropharyngeal numbness, unpleasant taste, or any other side effectnormally associated with administration of a local anesthetic followingintranasal administration.

[0396] The same amount of the mixture was dorsonasally administered tofive patients afflicted with headaches. Each of these five patientsexperienced complete or nearly complete inhibition of head pain andother symptoms of their headaches within ten minutes followingadministration.

EXAMPLE 7

[0397] Dorsonasal Headache Treatment Using Lidocaine

[0398] Three headache patients were treated by delivering about 20-50milligrams of a 10% (w/v) lidocaine solution to each nostril of thepatients. The solution was administered by spraying it through a plasticcannula which had been bent to conform its shape such that the outlet ofthe cannula was located dorsonasally. The cannula was inserted into eachnostril, and the solution was sprayed through the cannula, exitingtherefrom through the outlet. All three patients experienced rapidrelief from their headache symptoms; however, headache symptomsrebounded in two of the patients in less than one hour.

EXAMPLE 8

[0399] Dorsonasal Headache Treatment Using Bupivacaine

[0400] Two different headache patients were treated by delivering about0.25-0.75 milliliters of a 0.75% (w/v) bupivacaine solution to eachnostril of the patients. The solution was administered by passing thesolution along a plastic cannula having an absorbent portion affixed atthe distal (i.e., outlet) portion thereof. This cannula had also beenbent to conform its shape such that the outlet of the cannula and theaffixed absorbent portion were located dorsonasally. The solution waspassed along the cannula, and the cannula was left in place for severalminutes. Both of these patients experienced rapid relief from theirheadache symptoms, and neither patient experienced rebound of headachesymptoms within about one day, the end of the follow-up period for thesepatients.

[0401] The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety.

[0402] While this invention has been disclosed with reference tospecific embodiments, it is apparent that other embodiments andvariations of this invention may be devised by others skilled in the artwithout departing from the true spirit and scope of the invention. Theappended claims are intended to be construed to include all suchembodiments and equivalent variations.

What is claimed is:
 1. An intranasal drug delivery device comprising abody having a shape which conforms to the shape of the nasal cavity of ahuman, the body having a proximal end and a distal portion having adistal end, the distal portion being curved or angled with respect to alongitudinal axis of the body, the longitudinal axis of body at thedistal end forming an angle of about 90 degrees to about 170 degreeswith respect to the longitudinal axis at the proximal end prior toinsertion of the distal end into the nasal cavity, such that when thedistal portion of the body is in the apex of the nasal cavity, thedistal end faces a posterior portion of the nasal cavity, wherein thedevice is adapted for directed intranasal delivery of the drug, andwherein the distal portion can be urged through a nostril of the humaninto the apex of the nasal cavity without injuring the human.
 2. Thedevice of claim 1, wherein the body is substantially rigid.
 3. Thedevice of claim 1, wherein the body is flexible.
 4. The device of claim1, wherein the body comprises a flexible portion.
 5. The device of claim1, wherein a lumen extends longitudinally within the body from theproximal end thereof to an outlet port at the exterior surface of thebody.
 6. The device of claim 5, wherein the outlet port is on the distalportion of the body.
 7. The device of claim 5, wherein the lumen extendslongitudinally within the body from the proximal end thereof to aplurality of outlet ports at the exterior surface of the body.
 8. Thedevice of claim 5, wherein a plurality of lumens extend longitudinallywithin the body from the proximal end thereof, and wherein each lumenextends from the proximal end of the body to a separate outlet port. 9.The device of claim 8, wherein at least one outlet portion is at thedistal end of the body.
 10. The device of claim 5, wherein at least oneoutlet port is situated on the distal portion of the body in anorientation such that when the distal portion of the body is in the apexof the nasal cavity, the outlet port faces a posterior portion of thenasal cavity.
 11. The device of claim 10, wherein the posterior portionof the nasal cavity is the sphenoethmoidal recess.
 12. The device ofclaim 5, wherein at least one outlet port is situated on the distalportion of the body in an orientation such that when the distal portionof the body is in the apex of the nasal cavity, the outlet port faces asuperior portion of the nasal cavity.
 13. The device of claim 1, whereinthe distal end of the body is rounded.
 14. The device of claim 1,wherein the longitudinal axis of the body at the distal portion thereofforms an angle of from about 110 to about 160 degrees with thelongitudinal axis of the body at the proximal end thereof.
 15. Thedevice of claim 14, wherein the longitudinal axis of the body at thedistal portion thereof forms an angle of from about 120 to about 150degrees with the longitudinal axis of the body at the proximal endthereof.
 16. The device of claim 1, wherein the proximal portion of thebody has an indicium for indicating the orientation of the distalportion of the body.
 17. The device of claim 5, further comprising anextendable instrument situated with the lumen, wherein the extendableinstrument is extendable through the outlet port.
 18. The device ofclaim 17, wherein the extendible instrument is selected from the groupconsisting of a swab, a rosette, an inflatable balloon, and a needle.19. The device of claim 18, wherein the needle is hollow, has an outletin a distal end thereof, extends through the lumen, has a proximal end,and is connectable at its proximal end to a reservoir.
 20. The device ofclaim 19, wherein the reservoir is selected from the group consisting ofa compressible reservoir, a deformable bulb, and a syringe.
 21. Thedevice of claim 1, wherein the body has an absorbent portion on thedistal portion.
 22. The device of claim 5, wherein the lumencommunicates at the proximal end of the body with the interior of areservoir containing a pharmaceutical composition.
 23. The device ofclaim 22, wherein the pharmaceutical composition comprises a long-actinglocal anesthetic.
 24. The device of claim 22, wherein the pharmaceuticalcomposition is delivered in a form selected from the group consisting ofa liquid, a gel, a foam, a mousse, a powder, a dispersed powder, anatomized liquid, an aerosol, and a liposomal preparation.
 25. A methodof intranasally administering a composition to a selected portion of thenasal epithelium of a human patient, the method comprising inserting theintranasal drug delivery device of claim 1 into a nostril of thepatient, wherein the composition is present on at least a portion of theexterior surface of the body at the distal portion thereof, urging thedevice through the nostril such that the distal portion of the body isin the apex of the nasal cavity, and contacting the selected portion ofthe nasal epithelium with the composition on the portion of the exteriorsurface.
 26. A method of intranasally administering a composition to aselected portion of the nasal epithelium of a human patient, the methodcomprising inserting the intranasal drug delivery device of claim 1 intoa nostril of the patient, wherein the distal portion of the deviceincludes an outlet port facing the selected portion of the nasalepithelium and a lumen extending in the body from the proximal endthereof to the outlet port, urging the device through the nostril suchthat the distal portion of the body is in the apex of the nasal cavity,and providing the composition to the selected portion of the nasalepithelium through the outlet port by way of the lumen.
 27. A method ofintranasally administering a composition to a selected portion of thenasal epithelium of a human patient, the method comprising inserting theintranasal drug delivery device of claim 1 into a nostril of thepatient, wherein the device has a lumen extending in the body from theproximal end thereof to an outlet port on the distal portion thereof,urging the device through the nostril such that the distal portion ofthe body is in the apex of the nasal cavity and the outlet port facesthe selected portion of the nasal epithelium, and urging an elongateinstrument through the lumen, wherein the elongate instrument isselected from the group consisting of an extendable instrumentcomprising the composition, a swab impregnated with the composition, arosette impregnated with the composition, a needle coated with thecomposition, an inflatable instrument comprising the composition, aballoon coated with the composition, a balloon impregnated with thecomposition, a hollow instrument having a lumen for providing thecomposition, and a hollow needle having a needle lumen for providing thecomposition, whereby the composition is provided to the selected portionof the nasal epithelium.
 28. An anatomically adapted intranasal deliverynozzle for intranasally administering a composition to a selectedportion of the nasal epithelium of a human patient, the nozzlecomprising a body having a delivery lumen extending therethrough from aproximal end of the body to an outlet port at a distal portion of thebody, and an exterior portion having (i) a flattened portion situatedperipherally between the proximal end and the distal portion for seatingthe nozzle against the nasal septum of the patient, (ii) an anteriorportion situated peripherally between the proximal end and the distalportion for seating the nozzle against a portion of the external nasalcartilage of the patient, and (iii) an indented portion situatedperipherally between the proximal end and the distal portion for seatingthe nozzle against a nasal concha of the patient, wherein when thenozzle is seated, the outlet port is situated within the nasal cavity ofthe patient such that an axis extending through the discharge port isoffset from the apex of the nasal cavity by no more than about 30degrees.
 29. The nozzle of claim 28, wherein when the nozzle is seated,the outlet port is situated within the nasal cavity of the patient suchthat the axis extending through the discharge port is offset from theapex of the nasal cavity by no more than about 15 degrees.
 30. Thenozzle of claim 28, wherein the body further includes a distal seatingportion for seating the nozzle against the superior surface of the nasalcavity, wherein when the nozzle is seated, the outlet port is situatedwithin the nasal cavity of the patient such that the axis extendingthrough the discharge port is offset from the apex of the nasal cavityby no more than about 30 degrees.
 31. The nozzle of claim 28, whereinthe body is deformable.
 32. The nozzle of claim 31, wherein the body isdeformable at a certain condition, but is less deformable at a differentcondition, whereby the nozzle may be adapted to the nasal cavity of thepatient at the certain condition and thereafter used at the differentcondition.
 33. The nozzle of claim 32, wherein the body is adapted tothe nasal cavity of the patient at a temperature at which the body isdeformable, and wherein the body is thereafter used at a temperature atwhich the body is less deformable.
 34. A method of intranasallyadministering a composition to a selected portion of the nasalepithelium of a human patient, the method comprising a) seating withinthe nasal cavity of the patient an anatomically adapted intranasaldelivery nozzle, the nozzle comprising a body having a delivery lumenextending therethrough from a proximal end of the body to an outlet portat a distal portion of the body, and an exterior portion having (i) aflattened portion situated peripherally between the proximal end and thedistal portion for seating the nozzle against the nasal septum of thepatient, (ii) an anterior portion situated peripherally between theproximal end and the distal portion for seating the nozzle against aportion of the external nasal cartilage of the patient, and (iii) anindented portion situated peripherally between the proximal end and thedistal portion for seating the nozzle against a nasal concha of thepatient, wherein when the nozzle is seated, the outlet port is situatedwithin the nasal cavity of the patient such that the axis extendingthrough the discharge port is offset from the apex of the nasal cavityby no more than about 30 degrees, and thereafter b) providing thecomposition to the delivery lumen, whereby the composition isintranasally administered to the selected portion of the nasalepithelium of the patient.
 35. A systemic drug delivery devicecomprising a body having a shape which conforms to the shape of thenasal cavity of a human, the body having a proximal end and a distalportion which can be urged through a nostril of the human into the apexof the nasal cavity without injuring the human, the distal portionhaving a distal end and being curved or angled with respect to alongitudinal axis of the body, the longitudinal axis of body at thedistal end forming an angle of about 90 degrees to about 170 degreeswith respect to the longitudinal axis at the proximal end prior toinsertion of the distal end into the nasal cavity, such that when thedistal portion of the body is in the apex of the nasal cavity, thedistal portion faces a portion of the nasal cavity for directedintranasal delivery of the drug, wherein the body has an applicatorportion in the form of at least one of (a) a portion on which the drugis present, (b) a portion to which the drug may be supplied, and (c) alumen through which the drug may be delivered, the applicator portionbeing adapted for location in close anatomic proximity to a highlyvascularized portion of the nasal epithelium when the distal portion ofthe body is in the apex of the nasal cavity.
 36. A method of inhibitinga cerebral neurovascular disorder in a human patient, the methodcomprising intranasally administering to the patient a long-acting localanesthetic pharmaceutical composition in an amount effective to inhibitthe cerebral neurovascular disorder, wherein the long-acting localanesthetic pharmaceutical composition further comprises a compoundselected from the group consisting of an anti-epileptic, phenytoinsodium, a serotonin receptor agonist, a serotonin subclass 5HT1Freceptor agonist, LY334,370, a sesquiterpene lactone, parthanolide,Tanacetum parthenium, and an extract of Tanacetum parthenium.
 37. Themethod of claim 36, wherein the cerebral neurovascular disorder isselected from the group consisting of tinnitus, cerebrovascular spasm,seizure, a disorder manifested during or after and associated with anacute ischemic event, and a neurovascular headache.
 38. The method ofclaim 37, wherein the cerebral neurovascular disorder is a neurovascularheadache.
 39. The method of claim 38, wherein the neurovascular headacheis selected from the group consisting of a migraine, a cluster headache,and a headache associated with a vascular disease.
 40. The method ofclaim 39, wherein the neurovascular headache is a migraine.
 41. Themethod of claim 36, wherein the cerebral neurovascular disorder is anacute cerebral neurovascular disorder.
 42. The method of claim 41,wherein the acute cerebral neurovascular disorder is selected from thegroup consisting of a tinnitus episode, an individual seizure, anepisode of cerebrovascular spasm, an acute migraine episode, anindividual headache episode associated with a cluster headache, and anindividual headache associated with a vascular disease.
 43. The methodof claim 42, wherein the acute cerebral neurovascular disorder is anacute migraine episode.
 44. The method of claim 36, wherein the compoundis an anti-epileptic.
 45. The method of claim 36, wherein the compoundis phenytoin sodium.
 46. The method of claim 36, wherein the compound isa serotonin receptor agonist.
 47. The method of claim 36, wherein thecompound is a sesquiterpene lactone.
 48. The method of claim 36, whereinthe compound is parthanolide.
 49. The method of claim 36, wherein thecompound is Tanacetum parthenium.
 50. The method of claim 36, whereinthe compound is an extract of Tanacetum parthenium.
 51. A method ofinhibiting a cerebral neurovascular disorder in a human patient, themethod comprising energizing a dorsonasally implanted electronic neuralstimulator.
 52. A local anesthetic compound having the chemicalstructure of formula (IV), wherein R is ethyl, phenyl, or C₅-C₈straight- or branched-chain alkyl, and R′ is 2,6-dimethylphenyl,thiophene, or 2,5-dimethylthiophene, and wherein R″ and R′″ are selectedsuch that either each of R″ and R′″ is a straight-chain alkyl wherein R″and R′″ have a total of 4 to 6 carbon atoms, or R″ and R′″ together forma heteroalkyl ring having a total of 5 to 7 carbon atoms and a nitrogenatom.


53. The local anesthetic compound of claim 52, wherein the compound hasthe structure of formula (III)


54. A kit comprising a long-acting local anesthetic pharmaceuticalcomposition and a dorsonasal drug delivery device for administering thecomposition to an animal.
 55. The kit of claim 54, further comprising aninstructional material which describes dorsonasal administration of thecomposition.
 56. The kit of claim 54, wherein the dorsonasal drugdelivery device is selected from the group consisting of: a) adorsonasal drug delivery device comprising a body having a shape whichconforms to the shape of the nasal cavity of a human, the body having aproximal end and a distal portion having a distal end, wherein thedistal portion can be urged through a nostril of the human into the apexof the nasal cavity without injuring the human; and b) an anatomicallyadapted dorsonasal delivery nozzle for dorsonasally administering acomposition to a human patient, the nozzle comprising a body having adelivery lumen extending therethrough from a proximal end of the body toan outlet port at a distal portion of the body, and an exterior portionhaving (i) a flattened portion situated peripherally between theproximal end and the distal portion for seating the nozzle against thenasal septum of the patient, (ii) an anterior portion situatedperipherally between the proximal end and the distal portion for seatingthe nozzle against a portion of the external nasal cartilage of thepatient, and (iii) an indented portion situated peripherally between theproximal end and the distal portion for seating the nozzle against anasal concha of the patient, wherein when the nozzle is seated, theoutlet port is situated within the nasal cavity of the patient such thatan axis extending through the discharge port is offset from the apex ofthe nasal cavity by no more than about 30 degrees.
 57. A method ofinhibiting cephalic inflammation in a human patient, the methodcomprising intranasally administering to the patient a long-acting localanesthetic pharmaceutical composition in an amount effective to inhibitthe cephalic inflammation.
 58. A method of inhibiting cephalicinflammation in a human patient, the method comprising anesthetizing anerve structure associated with the disorder in the patient for a periodeffective to inhibit the inflammation.
 59. A method of inhibitingcephalic inflammation in a human patient, the method comprisingenergizing a dorsonasally implanted electronic neural stimulator.